Genetic sequences and proteins related to alzheimer&#39;s disease

ABSTRACT

The present invention describes the identification, isolation and cloning of two human presenilin genes, PS-1 and PS-2, mutations in which lead to Familial Alzheimer&#39;s Disease. Also identified are presenilin homologue genes in mice, C. elegans and D. melanogaster. Transcripts and products of these genes are useful in detecting and diagnosing Alzheimer&#39;s disease, developing therapeutics for treatment of Alzheimer&#39;s disease, as well as the isolation and manufacture of the protein and the constructions of transgenic animals expressing the mutant genes.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-In-Part of U.S. application Ser. No.08/509,359, entitled GENETIC SEQUENCES AND PROTEINS RELATED TOALZHEIMER'S DISEASE (Inventors: Peter H. St. George-Hyslop, Johanna M.Rommens and Paul E. Fraser), filed on Jul. 31, 1995, which was aContinuation-In-Part of U.S. application Ser. No. 08/496,841, entitledGENETIC SEQUENCES AND PROTEINS RELATED TO ALZHEIMER'S DISEASE(Inventors: Peter H. St. George-Hyslop, Johanna M. Rommens and Paul E.Fraser), filed on Jun. 28, 1995, which was a Continuation-in-Part ofU.S. application Ser. No. 08/431,048, entitled GENETIC SEQUENCES ANDPROTEINS RELATED TO ALZHEIMER'S DISEASE (Inventors: Peter H. St.George-Hyslop, Johanna M. Rommens and Paul E. Fraser), filed on Apr. 28,1995, all of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to the field of neurological andphysiological dysfunctions associated with Alzheimer's Disease. Moreparticularly, the invention is concerned with the identification,isolation and cloning of genes which when mutated are associated withAlzheimer's Disease as well as their transcripts, gene products andassociated sequence information and neighbouring genes. The presentinvention also relates to methods for diagnosing and detecting carriersof the genes, and to Alzheimer's Disease diagnosis and gene therapyusing recombinant technologies and therapy using the information derivedfrom the DNA, protein, and the metabolic function of the protein.

BACKGROUND OF THE INVENTION

In order to facilitate reference to various journal articles, a listingof the articles is provided at the end of this specification.

Alzheimer's Disease (AD) is a degenerative disorder of the human centralnervous system characterized by progressive memory impairment andcognitive and intellectual decline during mid to late adult life(Katzman, 1986). The disease is accompanied by a constellation ofneuropathologic features principal amongst which are the presence ofextracellular amyloid or senile plaques and the neurofibriliarydegeneration of neurons. The etiology of this disease is complex,although in some families it appears to be inherited as an autosomaldominant trait. However, even amongst these inherited forms of AD, thereare at least three different genes which confer inherited susceptibilityto this disease (St. George-Hyslop et al., 1990). The ε4 (Cys112Arg)allelic polymorphism of the Apolipoprotein E (ApoE) gene has beenassociated with AD in a significant proportion of cases with onset latein life (Saunders et al., 1993; Strittmatter et al., 1993). Similarly, avery small proportion of familial cases with onset before age 65 yearshave been associated with mutations in the β-amyloid precursor protein(APP) gene (Chartier-Harlin et al., 1991; Goate et al., 1991; Murrell etal., 1991; Karlinsky et al., 1992; Mullan et al., 1992). A third locus(AD3) associated with a larger proportion of cases with early onset ADhas recently been mapped to chromosome 14q24.3 (Schellenberg et al.,1992; St George-Hyslop et al., 1992; Van Broeckhoven et al., 1992).

Although chromosome 14q carries several genes which could be regarded ascandidate genes for the site of mutations associated with AD3 (e.g.cFOS, alpha-1-antichymotrypsin, and cathepsin G), most of thesecandidate genes have been excluded on the basis of their physicallocation outside the AD3 region and/or the absence of mutations in theirrespective open reading frames (Schellenberg, G D et al., 1992; VanBroeckhoven, C et al., 1992; Rogaev et al., 1993; Wong et al., 1993).

There have been several developments and commercial directions inrespect of treatment of Alzheimer's Disease and diagnosis thereof.Published PCT application WO 94 23049 describes transfection of highmolecular weight YAC DNA into specific mouse cells. This method is usedto analyze large gene complexes, for example the transgenic mice mayhave increased amyloid precursor protein gene dosage, which mimics thetrisomic condition that prevails in Downs Syndrome, and allows thegeneration of animal models with β-amyloidosis similar to that prevalentin individuals with Alzheimer's Disease. Published internationalapplication WO 94 00569 describes transgenic non-human animalsharbouring large transgenes such as the transgene comprising a humanamyloid precursor protein gene. Such animal models can provide usefulmodels of human genetic diseases such as Alzheimer's Disease.

Canadian Patent application No. 2096911 describes a nucleic acid codingfor amyloid precursor protein-cleaving protease, which is associatedwith Alzheimer's Disease and Down's syndrome. The genetic informationmay be used to diagnose Alzheimer's Disease. The genetic information wasisolated from chromosome 19. Canadian patent application 2071105,describes detection and treatment of inherited or acquired Alzheimer'sDisease by the use of YAC nucleotide sequences. The YACs are identifiedby the numbers 23CB 10, 28CA12 and 26FF3.

U.S. Pat. No. 5,297,562, describes detection of Alzheimer's Diseaseassociated with trisomy of chromosome 21. Treatment involves methods forreducing the proliferation of chromosome 21 trisomy. Canadian Patentapplication No. 2054302 describes monoclonal antibodies which recognizea human brain cell nucleus protein encoded by chromosome 21 and are usedto detect changes or expression due to Alzheimer's Disease or Down'sSyndrome. The monoclonal antibody is specific to a protein encoded byhuman chromosome 21 and is found in large pyramidal cells of human braintissue.

SUMMARY OF THE INVENTION

By extensive effort and a unique approach to investigating the AD3region of chromosome 14q, the Alzheimer's related membrane protein(ARMP) gene (or presenilin I (PS1) gene has been isolated, cloned andsequenced from within the AD3 region on chromosome 14q24.3. In addition,direct sequencing of RT-PCR products spanning this 3.0 kb cDNAtranscript isolated from affected members of at least eight largepedigrees linked to chromosome 14, has led to the discovery of missensemutations in each of these different pedigrees. These mutations areabsent in normal chromosomes. It has now been established that the PS1(or ARMP) gene is causative of familial Alzheimer's Disease type AD3. Inrealizing this link, it is understood that mutations in this gene can beassociated with other cognitive, intellectual, or psychological diseasessuch as cerebral hemorrhage, schizophrenia, depression, mentalretardation and epilepsy. These clinical diagnoses and phenotypes arepresent in these AD families and these phenotypes have been seen inmutations of the APP protein gene. The Amyloid Precursor Protein (APP)gene is also associated with inherited Alzheimer's Disease. Theidentification of both normal and mutant forms of the PS1 gene and geneproducts has allowed for the development of screening and diagnostictests for PS1 utilizing nucleic acid probes and antibodies to the geneproduct. Through interaction with the defective gene product and thepathway in which this gene product is involved, gene therapy,therapeutic intervention, manipulation and delivery are now madepossible.

A second gene associated with AD has now been identified on humanchromosome 1. This gene, the ES-1 or presenilin II (PS2) gene, also hasbeen isolated and cloned. Mutations of this gene have been identified inpatients with early onset familial AD. The PS2 (or ES-1) gene andprotein have been shown to have high degrees of sequence homology atboth the nucleic acid and amino acid sequence levels, and share majorstructural similarities, including conserved regions, tissue-specificalternative splicing patterns and predicted tertiary structure. Thus,they are believed to be representatives of a new gene family, thepresenilins.

Non-human homologues of the PS1 and PS2 genes and proteins have now beenidentified, isolated and cloned. Amongst those disclosed herein are themurine homologue (PS1) of human PS1, a C. elegans member (SEL-12), and aD. melanogaster member (DmPS) of the presenilin gene family. Each ofthese genes and proteins have been identified on the basis of their highdegrees of homology to the PS1/PS2 genes.

Various aspects of the invention are summarized as follows. Inaccordance with a first aspect of the invention, a purified mammalianpolynucleotide is provided which codes for Alzheimer's related membraneprotein (ARMP) or presenilin I (PS1). The polynucleotide has a sequencewhich is the functional equivalent of the DNA sequence of ATCC deposit97124, deposited Apr. 28, 1995. The mammalian polynucleotide may be inthe form of DNA, genomic DNA, cDNA, mRNA and various fragments andportions of the gene sequence encoding PS1. The mammalian DNA isconserved in many species, including humans and rodents, for examplemice; the DNA is conserved also in all other non-mammalian vertebratesand most invertebrate organisms.

Purified human nucleotide sequences which encode mutant PS1 includethose having mutations at nucleotide position (i) 685, A→C (A isreplaced by C); (ii) 737, A→G; (iii) 986, C→A, iv) 1105, C→G; (v) 1478,G→A; (vi) 1027, C→T; (vii) 1102, C→T; and (viii) 1422, C→G of SEQ ID NO:1 as well as in the cDNA sequence of a further human clone of a sequenceidentified by SEQ ID NO: 133.

The nucleotide sequences encoding both PS1 and PS2 have an alternativesplice form in the gene's open reading frame. The human cDNA sequencewhich codes for PS1 has SEQ ID NO:1 as well as SEQ ID NO:133 assequenced in another human clone. The mouse sequence which encodes mPS1has SEQ ID NO:3, as well as SEQ ID NO:135 derived from a further clonecontaining the entire coding region. Various DNA and RNA probes andprimers may be made from appropriate polynucleotide lengths selectedfrom the sequences. Portions of the sequence also encode antigenicdeterminants of these presenilins.

Suitable expression vectors comprising the nucleotide sequences areprovided along with suitable host cells transfected with such expressionvectors.

In accordance with another aspect of the invention, purified mammalianAlzheimer's related membrane protein (ARMP) or presenilin I (PS1) isprovided. The purified protein has an amino acid sequence encoded bypolynucleotide sequence as identified above which for the human is SEQID NO:2 and SEQ ID NO:133 (derived from another clone). The mouse PS1amino acid sequence is defined by SEQ ID NO:2 and SEQ ID NO:4, thelatter being translated from another clone containing the entire codingregion. The purified protein may have substitution mutations selectedfrom the group consisting of the following positions identified in SEQID NO:2 and SEQ ID NO:133: (i) M 146 L; (ii) H 163 R; (iii) A 246 E;(iv) L 286 V; (v) C 410 Y; (vi) A 260 V; (vii) A 285 V; and (viii) L 392V.

In accordance with another aspect of the invention, polyclonal andmonoclonal antibodies raised to specific predicted sequences of thepresenilin proteins are provided. Polypeptides of at least six aminoacid residues are provided. The polypeptides of six or greater aminoacid residues may define antigenic epitopes of a presenilin. Monoclonalantibodies having suitably specific binding affinity for the antigenicregions of a presenilin are prepared by use of corresponding hybridomacell lines. In addition, other polyclonal antibodies may be prepared byinoculation of animals with suitable peptides or holoprotein which addsuitable specific binding affinities for antigenic regions of apresenilin.

In accordance with another aspect of the invention, an isolated DNAmolecule is provided which codes for E5-1 protein.

In accordance with another aspect of the invention, purified PS2 proteinis provided, having amino acid SEQ ID NO:137.

In accordance with another aspect of the invention a bioassay isprovided for determining if a subject has a normal or mutant PS1 or PS2,where the bioassay comprises providing a biological sample from thesubject, conducting a biological assay on the sample to detect a normalor mutant gene sequence coding for PS1 or PS2, a normal or mutant PS1 orPS2 amino acid sequence, or a normal or defective protein function.

In accordance with another aspect of the invention, a process isprovided for producing PS1 or PS2 comprising culturing one of the abovedescribed transfected host cells under suitable conditions, to producethe presenilin by expressing the DNA sequence. Alternatively, a PS1 orPS2 protein may be isolated from mammalian cells in which the presenilinis normally expressed.

In accordance with another aspect of the invention, is a therapeuticcomposition comprising PS1 or PS2 and a pharmaceutically acceptablecarrier.

In accordance with another aspect of the invention, a recombinant vectorfor transforming a mammalian tissue cell to express therapeuticallyeffective amounts of PS1 or PS2 in the cells is provided. The vector isnormally delivered to the cells by a suitable vehicle. Suitable vehiclesinclude vaccinia virus, adenovirus, adeno associated virus, retrovirus,liposome transport, neuraltropic viruses, Herpes simplex virus and othervector systems.

In accordance with another aspect of the invention, a method of treatinga patient deficient in normal PS1 or PS2 comprising administering to thepatient a therapeutically effective amount of the protein targeted at avariety of patient cells which normally express the presenilin. Theextent of administration of normal PS1 or PS2 being sufficient tooverride any effect the presence of the mutant presenilin may have onthe patient. As an alternative to protein, suitable ligands andtherapeutic agents such as small molecules and other drug agents may besuitable for drug therapy designed to replace the protein and defectivepresenilin, displace mutant presenilin, or to suppress its formation.

In accordance with another aspect of the invention, an immunotherapy fortreating a patient having Alzheimer's Disease comprises treating thepatient with antibodies specific to the mutant presenilin to reducebiological levels or activity of the mutant protein in the patient. Tofacilitate such amino acid therapy, a vaccine composition may beprovided for evoking an immune response in a patient of Alzheimer'sDisease where the composition comprises a mutant PS1 and apharmaceutically acceptable carrier with or without a suitableexcipient. The antibodies developed specific to the mutant PS1 could beused to target appropriately encapsulated drugs/molecules, specificcellular/tissue sites. Therapies utilizing specific ligands which bindto normal or wild type PS1 and which augment normal function of PS1 inmembranes and/or cells or inhibits the deleterious effect of the mutantprotein are also made possible.

In accordance with another aspect of the invention, a transgenic animalmodel for Alzheimer's Disease which has the mammalian polynucleotidesequence with at least one mutation which when expressed results inmutant PS1 or PS2 in the animal cells and thereby manifests a phenotype.For example, the human Prion gene when over-expressed in rodentperipheral nervous system and muscle cells causes a quite differentresponse in the animal than the human. The animal may be a rodent and ispreferably a mouse, but may also be other animals including rat, pig, D.melanogaster, C. elegans (nematode), all of which are used fortransgenic models. Yeast cells can also be used in which a presenilinsequence is expressed from an artificial vector.

In accordance with another aspect of the invention a transgenic mousemodel for Alzheimer's Disease has the mouse gene encoding a human ormurine PS1 or PS2 homologue mutated to manifest the symptoms. Thetransgenic mouse may exhibit symptoms of cognitive memory loss orbehavioural disturbances. In addition or alternatively, the symptoms mayappear as another cellular tissue disorder such as in mouse liver,kidney, spleen, bone marrow or other organs in which the presenilin geneproduct is normally expressed.

In accordance with another aspect of the invention, the presenilinproteins and nucleic acids may be used in the screening of smallmolecules which will be candidates for drug therapy of Alzheimer's andrelated diseases. In one series of embodiments, small molecules may bescreened for their ability to bind to a persenilin, especially human PS1or PS2. In particular, assays are provided which may be used to identifysmall molecules which will bind selectively or preferentially to eitherthe normal or mutant forms of PS1 or PS2. Such small molecules may befurther tested using the animal models disclosed mergon to furtherevaluate their therapeutic utility. In another series of embodiments,compounds may be tested for their ability to induce or respressexpression of the presenilins, especially human PS1 or PS2. Thus, assaysare provided in which the ability of a compound to alter the levels ofpresenilin mRNA transcripts or protein in a cell or cell culture istested. In preferred embodiments, the 5' regulatory region of apresenilin gene, especially a human PS1 or PS2 gene, are operativelyjoined to a reporter gene and cells are transformed with thisrecombinant construct. Such recombinant cells may then be used in highthrough-put assays for compounds which affect the expression of thepresenilins.

In accordance with another aspect of the invention, the proteins of theinvention can be used as starting points for rational drug design toprovide ligands, therapeutic drugs or other types of small chemicalmolecules. Alternatively, small molecules or other compounds identifiedby the above-described screening assays may serve as "lead compounds" inrational drug design.

DETAILED DESCRIPTION OF THE INVENTION

Various aspects of the invention are described hereinafter with respectto the drawings wherein:

FIG. 1, panel A is a schematic drawing of the genomic physical andtranscriptional map of the AD3 region of chromosome 14. Genetic mapinter-marker genetic distances averaged for male and female meiosis areindicated in centiMorgans.

FIG. 1, panel B is a schematic drawing of the constructed physicalcontig map of overlapping genomic DNA fragments cloned into YACsspanning a FAD locus on chromosome 14q.

FIG. 1, panel C is a schematic drawing of regions of interest within theconstructed physical contig map.

FIG. 1, panel D is a schematic drawing of a transcriptional mapillustrating physical locations of the 19 independent longer cDNAclones.

FIG. 2, panel A is a reproduction of the output of an automatedfluorescent chromatogram representing the change in nucleic acids whichdirect the Met 146 Leu change in the amino acid sequence of the ARMP orPS1 gene.

FIG. 2, panel B is a reproduction of the output of an automatedfluorescent chromatogram representing the change in nucleic acids whichdirect the His 163 Ala change in the amino acid sequence of the gene.

FIG. 2, panel C is a reproduction of the output of an automatedfluorescent chromatogram representing the change in nucleic acids whichdirect the Ala 246 Glu change in the amino acid sequence of the gene.

FIG. 2, panel D is a reproduction of the output of an automatedfluorescent chromatogram representing the change in nucleic acids whichdirect the Leu 286 Val change in the amino acid sequence of the gene.

FIG. 2, panel E is a reproduction of the output of an automatedfluorescent chromatogram representing the change in nucleic acids whichdirect the Cys 410 Tyr change in the amino acid sequence of the gene.

FIG. 3, panel A is a representation of a hydropathy plot of the putativePS1 protein.

FIG. 3, panel B is a schematic drawing of a model for the structuralorganization of the putative PS1 protein. Roman numerals depict thetransmembrane domains. Putative glycosylation sites are indicated asasterisks and most of the phosphorylation sites are located on the samemembrane face as the two acidic hydrophilic loops. The MAP kinase siteis present at residue 115 and the PKC site at residue 114. FAD mutationsites are indicated by horizontal arrows.

FIG. 4 is a schematic drawing of the predicted structure of the PS2protein.

FIG. 5A depicts an expression vector containing the entire ARMP cDNAsequence and includes the 5' untranslated region.

FIG. 5B depicts an expression vector containing a truncated ARMP cDNA inwhich the 5' untranslated region is replaced with an artificial Kozakconsensus sequence around the 5' cloning site.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In order to facilitate review of the various embodiments of theinvention and an understanding of the various elements and constituentsused in making and using the invention, the following terms used in theinvention description have the following meanings:

Alzheimer Related Membrane Protein (ARMP) or Presenilin-I (PS1)gene--the chromosome 14 gene which when mutated is associated withfamilial Alzheimer's Disease and/or other inheritable disease phenotypes(e.g. cerebral hemorrhage, mental retardation, schizophrenia, psychosis,and depression). This definition is understood to include sequencepolymorphisms wherein nucleotide substitutions in the gene sequence donot affect the essential function of the gene product, as well asfunctional equivalents of the nucleotide sequences of SEQ ID NO:1, SEQID NO:133, and SEQ ID NO:5. This term primarily relates to an isolatedcoding sequence, but can also include some or all of the flankingregulatory elements and/or introns. The term PS1 gene includes genes inother species analogous to this human gene which when mutated isassociated with Alzheimer's Disease. This gene is also referred to asthe ARMP gene, and sometimes as the S182 gene.

Alzheimer Related Membrane Protein (ARMP) or Presenilin-I Protein--theprotein encoded by the PS1 gene. This protein is also referred to asARMP. The preferred source of protein is the mammalian protein asisolated from human or other animal cells. Alternatively, functionallyequivalent proteins may exist in plants, insects and invertebrates (suchas C. elegans). The protein may be produced by recombinant organisms, orchemically or enzymatically synthesized. This definition is understoodto include the amino acid sequences of SEQ ID NO:2 and SEQ ID NO:134 andalso the various polymorphic forms of the protein wherein amino acidsubstitutions or deletions within the amino acid sequence do not affectthe essential functioning of the protein. The term also includesfunctional fragments of PS1 and functional equivalents of the PS1 aminoacid sequence.

Mutant PS1 gene--The PS1 gene containing one or more mutations whichtypically lead to Alzheimer's Disease and/or other inheritable diseasephenotypes (e.g. cerebral hemorrhage, mental retardation, schizophrenia,psychosis, and depression). This definition is understood to include thevarious mutations that exist, wherein nucleotide substitutions in thegene sequence affect the essential function of the gene product, as wellas mutations of functional equivalents of the nucleotide sequences ofSEQ ID NO:1, SEQ ID NO:133 and ID NO:5. This term primarily relates toan isolated coding sequence, but can also include some or all of theflanking regulatory elements' and/or introns.

Mutant PS1--a mammalian protein that is highly analogous to PS1 in termsof primary structure, but wherein one or more amino acid insertions,deletions and/or substitutions result in impairment of its essentialfunction, so that mammals, especially humans, whose PS1 producing cellsexpress mutant PS1 rather than the normal PS1, are predisposed todemonstrate the symptoms of Alzheimer's Disease and/or other relevantinheritable phenotypes (e.g. cerebral hemorrhage, mental retardation,schizophrenia, psychosis, and depression).

mPS1 gene--mouse gene analogous to the human PS1 gene. This definitionis understood to include sequence polymorphisms wherein nucleotidesubstitutions in the gene sequence do not affect the essential functionof the gene product, as well as functional equivalents of the nucleotidesequence of SEQ ID NO:135. This term primarily relates to an isolatedcoding sequence, but can also include some or all of the flankingregulatory elements and/or introns.

mPS1--mouse Alzheimer related membrane protein, encoded by the mPS1 geneand analogous to the human PS1. This definition is understood to includethe amino acid sequence of SEQ ID NO:4 and also the various polymorphicforms of the protein wherein amino acid substitutions, insertions, ordeletions within the amino acid sequence do not affect the essentialfunctioning of the protein. The term also includes functional fragmentsof the protein and functional equivalents of its amino acid sequence.

Mutant mPS1 gene--the mPS1 gene containing one or more mutations whichtypically lead to one or more amino acid insertions, deletions and/orsubstitutions resulting in impairment of the function of the mPS1protein. This definition is understood to include the amino acidsequence of SEQ ID NO:4 and also the various polymorphic forms of theprotein wherein amino acid substitutions or deletions within the aminoacid sequence do not affect the essential functioning of the protein.The term also includes functional fragments of the protein andfunctional equivalents of its amino acid sequence.

Mutant mPS1--a mouse protein which is highly analogous to mPS1 in termsof primary structure, but wherein one or more amino acid insertions,deletions and/or substitutions result in impairment of its essentialfunction, so that mice, whose mPS1 producing cells express mutant mPS1rather than the normal mPS1, are predisposed to demonstrate the symptomsof Alzheimer's Disease and/or other relevant inheritable phenotypes, orother phenotypes and behaviours as manifested in mice.

PS1 or PS2 carrier--a mammal in apparent good health whose chromosomescontain a mutant PS1 or PS2 gene that may be transmitted to offspringand which will, in most cases, develop Alzheimer's Disease in mid tolate adult life.

Missense mutation--A mutation of nucleic acid sequence which alters acodon to that of another amino acid, causing an altered translationproduct to be made.

Pedigree--In human genetics, a diagram showing the ancestralrelationships and transmission of genetic traits over severalgenerations in a family.

PS2 gene--the chromosome 1 gene which shows homology to the PS1 gene andwhich when mutated is associated with familial Alzheimer's Diseaseand/or other inheritable disease phenotypes. This definition isunderstood to include sequence polymorphisms wherein nucleotidesubstitutions in the gene sequence do not affect the essential functionof the gene product, as well as functional equivalents of the nucleotideSEQ ID NO:136. This term primarily relates to an isolated codingsequence, but can also include some or all of the flanking regulatoryelements and/or introns. This term also includes the gene in otherspecies analogous to the human gene described herein. This gene is alsoreferred to as the E5-1 gene.

PS2 protein--the protein encoded by the PS2 gene. This protein is alsoreferred to as E5-1. The term PS2 protein includes the protein of SEQ IDNO:137 and also the various polymorphic and splice variant forms of theprotein wherein amino acid substitutions or deletions within the aminoacid sequence do not affect the essential functioning of the protein.The term also includes functional fragments of the protein andfunctional equivalents of its amino acid sequence.

Mutant PS2 gene--the PS2 gene containing one or more mutations whichtypically lead to Alzheimer's Disease. This term is understood toinclude the various mutations that exist, wherein nucleotidesubstitutions, insertions, or deletions in the gene sequence affect theessential function of the gene product. This term primarily relates toan isolated coding sequence but can also include some or all of theflanking regulatory elements and/or introns.

Mutant PS2 protein--a protein analogous to PS2 protein but wherein oneor more amino acid insertions, deletions and/or substitutions result inimpairment of its essential function such that mammals, especiallyhumans, whose PS2-producing cells express mutant PS2 protein, arepredisposed to demonstrate the symptoms of Alzheimer's Disease.

DmPS gene--Drosophila melanogaster gene analogous to the human PS1 andPS2 genes. This definition is understood to include the amino acidsequence polymorphisms wherein nucleotide substitutions, insertions ordeletions in the gene sequence do not affect the essential function ofthe gene product, as well as functional equivalents of the nucleotidesequence, SEQ ID NO:165. This term primarily relates to an isolatedcoding sequence but can also include some or all of the flankingregulatory elements and/or introns.

DmPS protein--The protein encoded by the DmPS gene and analogous to thehuman presenilins. This definition is understood to include the aminoacid sequence of SEQ ID NO:166 and also the various polymorphic forms ofthe protein wherein amino acid substitutions, insertions or deletionswithin the amino acid sequence do not affect the essential functioningof the protein. The term also includes functional fragments of theprotein and functional equivalents of its amino acid sequence.

Mutant DmPS Gene--the DmPS gene containing one or more mutations whichlead to one or more amino acid insertions, deletions and/orsubstitutions resulting in impairment of the function of the DmPSprotein.

Mutant DmPS Protein--a D. melanogaster protein which is highly analogousto DmPS protein in terms of primary structure, wherein one or more aminoacid insertions, deletions and/or substitutions result in impairment ofits essential function.

Functional Equivalent--as used in describing gene sequences and aminoacid sequences means that a recited sequence need not be identical tothe definitive sequence of the SEQ ID NOs but need only provide asequence which functions biologically and/or chemically as theequivalent of the definitive sequence. Hence sequences which correspondto a definitive sequence may also be considered as functionallyequivalent sequence.

Linkage analysis--Analysis of co-segregation of a disease trait ordisease gene with polymorphic genetic markers of defined chromosomallocation.

hPS1 gene--human PS1 gene

ORF--open reading frame.

PCR--polymerase chain reaction.

contig--contiguous cloned regions

YAC--yeast artificial chromosome

RT-PCR--reverse transcription polymerase chain reaction.

SSR--Simple sequence repeat polymorphism.

Homology--typically measured using sequence analysis software (e.g.,Sequence Analysis Software Package of the Genetics Computer Group,University of Wisconsin Biotechnology Center, 1710 University Avenue,Madison, Wis. 53705). Such software matches similar sequences byassigning degrees of homology to various insertions, deletions,substitutions, and other modifications. Conservative substitutionstypically include substitutions within the following groups: glycine,alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid,asparagine, glutamine; serine, threonine; lysine, arginine; andphenylalanine, tyrosine.

Percent Identity--is a measure of the identity of any two amino acid ornucleic acid sequences over a defined length.

Protein and polypeptide--any chain of amino acids, regardless of lengthor post-translational modification (e.g., glycosylation orphosphorylation).

Substantially pure preparation--is a preparation which is at least 60%by weight (dry weight) the compound of interest. Preferably thepreparation is at least 75%, more preferably at least 90%, and mostpreferably at least 99%, by weight the compound of interest. Purity canbe measured by any appropriate method, e.g., column chromatography,polyacrylamide gel electrophoresis, or HPLC analysis.

Isolated DNA--is DNA that is not immediately contiguous with both of thecoding sequences with which it is immediately contiguous (one on the 5'end and one on the 3' end) in the naturally occurring genome of theorganism from which it is derived. The term therefore includes, forexample, a recombinant DNA which is incorporated into a vector; into anautonomously replicating plasmid or virus; or into the genomic DNA of aprokaryote or eukaryote, or which exists as a separate molecule (e.g., acDNA or a genomic DNA fragment produced by PCR or restrictionendonuclease treatment) independent of other sequences. It also includesa recombinant DNA which is part of a hybrid gene encoding additionalpolypeptide sequence.

Substantially identical amino acid sequence--is an amino acid sequencewhich differs only by conservative amino acid substitutions, forexample, substitution of one amino acid for another of the same class(e.g., valine for glycine, arginine for lysine, etc.) or by one or morenon-conservative substitutions, deletions, or insertions located atpositions of the amino acid sequence which do not destroy the functionof the protein (assayed, e.g., as described herein). Preferably, such asequence is at least 85%, more preferably 90%, and most preferably 95%identical at the amino acid level to the sequence of the protein orpeptide to which it is being compared. For nucleic acids, the length ofcomparison sequences will generally be at least 50 nucleotides,preferably at least 60 nucleotides, more preferably at least 75nucleotides, and most preferably 110 nucleotides. A "substantiallyidentical" nucleic acid sequence codes for a substantially identicalamino acid sequence as defined above.

Transformed cell--is a cell into which (or into an ancestor of which)has been introduced, by means of recombinant DNA techniques, a DNAmolecule encoding a protein of interest.

Operably Joined. A coding sequence and a regulatory region are said tobe operably joined when they are covalently linked in such a way as toplace the expression or transcription of the coding sequence under theinfluence or control of the regulatory region. If it is desired that thecoding sequences be translated into a functional protein, two DNAsequences are said to be operably joined if induction of promoterfunction results in the transcription of the coding sequence and if thenature of the linkage between the two DNA sequences does not (1) resultin the introduction of a frame-shift mutation, (2) interfere with theability of the regulatory region to direct the transcription of thecoding sequences, or (3) interfere with the ability of the correspondingRNA transcript to be translated into a protein. Thus, a regulatoryregion would be operably joined to a coding sequence if the regulatoryregion were capable of effecting transcription of that DNA sequence suchthat the resulting transcript might be translated into the desiredprotein or polypeptide.

Stringent Hybridization Conditions. Stringent hybridization conditionsis a term of art understood by those of ordinary skill in the art. Forany given nucleic acid sequence, stringent hybridization conditions arethose conditions of temperature and buffer solution which will permithybridization of that nucleic acid sequence to its complementarysequence and not to substantially different sequences. The exactconditions which constitute "stringent" conditions, depend upon thelength of the nucleic acid sequence and the frequency of occurrence ofsubsets of that sequence within other non-identical sequences. Byvarying hybridization conditions from a level of stringency at which nohybridization occurs to a level at which hybridization is firstobserved, one of ordinary skill in the art can, without undueexperimentation, determine conditions which will allow a given sequenceto hybridize only with identical sequences. Suitable ranges of suchstringency conditions are described in Krause, M. H.. and S. A.Aaronson, Methods in Enzymology, 200:546-556 (1991). Stringenthybridization conditions, depending upon the length and commonality of asequence, may include hybridization conditions of 30 C-60 C and from 5×to 0.1×SSC. Highly stringent hybridization conditions may includehybridixzation at 45 C and 0.1×SSC. Less than stringent hybridizationconditions are employed to isolate nucleic acid sequences which aresubstantially similar, allelic or homologous to any given sequence.

Purified antibody--is an antibody which is at least 60%, by weight, freefrom the proteins and naturally-occurring organic molecules with whichit is naturally associated. Preferably, the preparation is at least 75%,more preferably at least 90%, and most preferably at least 99%, byweight, antibody.

Specifically binds--means an antibody which recognizes and binds theprotein of interest but which does not substantially recognize and bindother molecules in a sample, e.g., a biological sample, which naturallyincludes the protein of interest.

The present invention is concerned with the identification andsequencing of the mammalian ARMP or presenilin I gene in order to gaininsight into the cause and etiology of Alzheimer's Disease, and toprovide screening methods and therapies for the diagnosis and treatmentof the disease can be developed. The gene has been identified, cDNAisolated and cloned, and its transcripts and gene products identifiedand sequenced. During such identification of the gene, considerablesequence information has also been developed on intron information inthe PS1 gene, flanking untranslated information and signal informationand information involving neighbouring genes in the AD3 chromosomeregion. Direct sequencing of overlapping RT-PCR products spanning thehuman gene isolated from affected members of large pedigrees linked tochromosome 14 has led to the discovery of missense mutations whichco-segregate with the disease.

Although it is generally understood that Alzheimer's Disease is aneurological disorder, most likely in the brain, expression of PS1 hasbeen found in a variety of human tissues such as heart, brain, placenta,lung, liver, skeletal muscle, kidney and pancreas. Although this gene isexpressed widely, the clinically apparent phenotype exists in brainalthough it is conceivable that biochemical phenotypes may exist inthese other tissues. As with other genetic diseases such as Huntington'sDisease and APP--Alzheimer's, the clinical disease manifestation mayreflect the different biochemistries of different cell types and tissues(which stem from genetics and the protein). Such findings suggest thatAD may not be solely a neurological disorder but may also be a systemicdisorder, hence requiring alternative therapeutic strategies which maybe targeted to other tissues or organs or generally in addition orseparately from neuronal or brain tissues.

The PS1 mutations identified have been related to Alzheimer's Diseasepathology. With the identification and sequencing of the gene and thegene product, probes and antibodies raised to the gene product can beused in a variety of hybridization and immunological assays to screenfor and detect the presence of either a normal or mutated gene or geneproduct.

Patient therapy through removal or blocking of the mutant gene product,as well as supplementation with the normal gene product byamplification, by genetic and recombinant techniques or by immunotherapycan now be achieved. Correction or modification of the defective geneproduct by protein treatment immunotherapy (using antibodies to thedefective protein) or knock-out of the mutated gene is now alsopossible. Familial Alzheimer's Disease could also be controlled by genetherapy in which the gene defect is corrected in situ or by the use ofrecombinant or other vehicles to deliver a DNA sequence capable ofexpressing the normal gene product, or a deliberately mutated version ofthe gene product whose effect counterbalances the deleteriousconsequences of the disease mutation to the affected cells of thepatient.

The present invention is also concerned with the identification andsequencing of a second human gene, the PS2 or presenilin II gene onchromosome 1, which is associated with Alzheimer's Disease.

Disease mechanism insights and therapies analogous to those describedabove in relation to the PS1 gene also are nonavailable as a result ofthe identification and isolation of the PS2 gene.

A homologue of the human presenilin I gene, mPS1, has been identified inmice and has been cloned and sequenced. Additionally, a homologue of thehuman presenilin genes, DmPS1, has been identified in D. melanogasterand its sequence determined.

The remainder of the "Description of the Preferred Embodiments" isorganized as follows.

1. Isolation of the Human PS1 (ARMP) Gene

a. Genetic mapping of the AD3 locus

b. Construction of a physical contig spanning the AD3 Region

c. Transcription mapping and preliminary analysis of candidate genes

d. Recovery of potential candidate genes

2. Characterization of the Human PS1 (ARMP) Gene

3. Identification of an alternate splice form of the PS1 (ARMP) geneproduct

4. Functional Domains of PS1 Protein

5. PS1 (ARMP) Protein

6. Mutations in the S182 (PS1) transcript

7. Isolation and Purification of PS1 (ARMP) Protein

8. Expression of PS1 (ARMP)

9. Antibodies to PS1 (ARMP)

10. Isolation of the Murine PS1 Gene

11. Transgenic Mouse Model of Alzheimer's Disease

12. Isolation of the Human PS2 (E5-1) Gene--A Homologue of the PS1 Gene

13. Mutations of the PS2 (E5-1) Gene associated with Alzheimer's Disease

14. PS2 (E5-1) Protein

15. Isolation and Purification of PS2 (ARMP) Protein

16. Antibodies to PS2 (E5-1)

17. Transgenic Mouse Model of PS2 (E5-1)-related Alzheimer's Disease

18. Functional Domains of Presenilins

19. Isolation of Presenilin Binding Proteins

a. direct extraction by affinity chromatography using GST-fusionproteins and synthetic peptides

b. co-isolation of presenilins and bound proteins by immunoprecipitation

c. Biomolecular Interaction Assay (BIAcore) utilizing a GST-fusioncapture system

d. Two-Hybrid yeast systems

20. Identification of Small Molecules with Presenilin Binding Capacity

21. Assays for Identifying Drugs Which Affect Presenilin Expression

22. Identification of a homologue of the ARMP (PS1) gene in C. elegans

23. Identification of a homologue of the PS1 (ARMP) gene in D.melanogaster

24. Screening for and Diagnosis of Alzheimer's Disease

a. General diagnostic Methods

b. Screening for Alzheimer's Disease Linked to Chromosome 14

c. Screening for Alzheimer's Disease Linked to Chromosome 1

25. Therapies

a. Rationale for Therapeutic, Diagnostic, and InvestigationalApplications of the PS1 and PS2 Genes and Gene Products as they Relateto the Amyloid Precursor Protein

b. Rationale for Therapeutic, Diagnostic, and InvestigationalApplications of the PS1 and PS2 Genes and the Products Thereof

c. Protein Therapy

d. Gene Therapy

26. EXAMPLES

a. Example 1: Development of the genetic, physical, "contig" andtranscriptional map of the minimal co-segregating region

b. Example 2: Cumulative two point lod scores for chromosome 14q24.3markers

c. Example 3: Haplotypes between flanking markers segregated with AD3 inFAD pedigrees

d. Example 4: Recovery of transcribed sequences from the AD3 interval

e. Example 5: Locating mutations in the ARMP (PS1) gene usingrestriction enzymes

f. Example 6: Locating mutations in the ARMP (PS1) gene using allelespecific oligonucleotides

g. Example 7: Northern hybridization demonstrating the expression ofARMP (PS1) mRNA in a variety of tissues

h. Example 8: Eukaryotic and prokaryotic expression vector systems

i. Example 9: Locating additional mutations in the ARMP (PS1) gene

j. Example 10: Antibody production

k. Example 11: Identification of mutations in the (PS2) E5-1 gene

l. Example 12: Transgenic Mice

m. Example 13: Expression of Recombinant PS1 and PS2 in Eukaryotic Cells

n. Example 14: Isolation of Presenilin Binding Proteins by AffinityChromatography

o. Example 15: Isolation of Presenilin Binding Proteins by Two-HybridYeast System

p. Example 16: Transgenic C. elegans

q. Example 17: Cloning of a Drosophila melanogaster homologue, DmPS, forthe Human Presenilin Genes

Isolation of the Human PS1 (ARMP) Gene

Genetic mapping of the AD3 locus.

After the initial regional mapping of the AD3 gene locus to 14q24.3 nearthe anonymous microsatellite markers D14S43 and D14S53 (Schellenberg, GD et al., 1992; St George-Hyslop, P et al., 1992; Van Broeckhoven, C etal., 1992), twenty one pedigrees were used to segregate AD as a putativeautosomal dominant trait (St George-Hyslop, P et al., 1992) and toinvestigate the segregation of 18 additional genetic markers from the14q24.3 region which had been organized into a high density geneticlinkage map (FIG. 1B) (Weissenbach et al., 1992; Gyapay et al., 1994).Pairwise maximum likelihood analyses previously published confirmedsubstantial cumulative evidence for linkage between familial Alzheimer'sDisease (FAD) and all of these markers (Table 1). However, much of thegenetic data supporting linkage to these markers were derived from sixlarge early onset pedigrees, FAD1 (Nee et al., 1983), FAD2 (Frommelt etal., 1991), FAD3 (Goudsmit et al., 1981; Pollen, 1993), FAD4 (Foncin etal., 1985), TOR1.1 (Bergamini, 1991) and 603 (Pericak-Vance et al.,1988) each of which provides at least one anonymous genetic marker from14q24.3 (St. George-Hyslop, P. et al 1992).

In order to define more precisely the location of the AD3 gene relativeto the known locations of the genetic markers from 14q24.3,recombinational landmarks were sought by direct inspection of the rawhaplotype data from those genotyped affected members of the sixpedigrees showing definitive linkage to chromosome 14. This selectivestrategy in this particular instance necessarily discards data from thereconstructed genotypes of deceased affected members as well as fromelderly asymptomatic members of the large pedigrees, and takes noaccount of the smaller pedigrees of uncertain linkage status. However,this strategy is very sound because it also avoids the acquisition ofpotentially misleading genotype data acquired either through errors inthe reconstructed genotypes of deceased affected members arising fromnon-paternity or sampling errors or from the inclusion of unlinkedpedigrees.

Upon inspection of the haplotype data for affected subjects, members ofthe six large pedigrees whose genotypes were directly determinedrevealed obligate recombinants at D14S48 and D14S53, and at D14S258 andD14S63. The single recombinant at D14S53, which depicts a telomericboundary for the FAD region, occurred in the same AD affected subject ofthe FAD1 pedigree who had previously been found to be recombinant atseveral other markers located telomeric to D14S53 including D14S48 (StGeorge-Hyslop, P et al., 1992). Conversely, the single recombinant atD14S258, which marks a centromeric boundary of the FAD region, occurredin an affected member of the FAD3 pedigree who was also recombinant atseveral other markers centromeric to D14S258 including D14S63. Bothrecombinant subjects had unequivocal evidence of Alzheimer's Diseaseconfirmed through standard clinical tests for the illness in otheraffected members of their families, and the genotype of both recombinantsubjects was informative and co-segregating at multiple loci within theinterval centromeric to D14S53 and telomeric to D14S258.

When the haplotype analyses were enlarged to include the reconstructedgenotypes of deceased affected members of the six large pedigrees aswell as data from the remaining fifteen pedigrees with probabilities forlinkage of less than 0.95, several additional recombinants were detectedat one or more marker loci within the interval between D14S53 andD14S258. Thus, one additional recombinant was detected in thereconstructed genotype of a deceased affected member of each of three ofthe larger FAD pedigrees (FAD1, FAD2 and other related families), andeight additional recombinants were detected in affected members of fivesmaller FAD pedigrees. However, while some of these recombinants mighthave correctly placed the AD3 gene within a more defined target region,it was necessary to regard these potentially closer "internalrecombinants" as unreliable not only for the reasons discussed earlier,but also because they provided mutually inconsistent locations for theAD3 gene within the D14S53-D14S258 interval.

Construction of a physical contig spanning the AD3 region.

As an initial step towards cloning the AD3 gene, a contig of overlappinggenomic DNA fragments cloned into yeast artificial chromosome vectors,phage artificial chromosome vectors and cosmid vectors was constructed(FIG. 1B). FISH mapping studies using cosmids derived from the YACclones 932c7 and 964f5 suggested that the interval most likely to carrythe AD3 gene was at least five megabases in size. Because the large sizeof this minimal co-segregating region would make positional cloningstrategies intractable, additional genetic pointers were sought whichfocused the search for the AD3 gene to one or more subregions within theinterval flanked by D14S53 and D14S258. Haplotype analyses at themarkers between D14S53 and D14S258 failed to detect statisticallysignificant evidence for linkage disequilibrium and/or allelicassociation between the FAD trait and alleles at any of these markers,irrespective of whether the analyses were restricted to those pedigreeswith early onset forms of FAD, or were generalized to include allpedigrees. This result was not unexpected given the diverse ethnicorigins of our pedigrees. However, when pedigrees of similar ethnicdescent were collated, direct inspection of the haplotypes observed onthe disease-bearing chromosome segregating in different pedigrees ofsimilar ethnic origin revealed two clusters of marker loci (Table 2).The first of these clusters located centromeric to D14S77 (D14S786,D14S277 and D14S268) and spanned the 0.95 Mb physical interval containedin YAC 78842 (depicted as region B in FIG. 1C). The second cluster waslocated telomeric to D14S77 (D14S43, D14S273, and D14S76) and spannedthe ˜1 Mb physical interval included within the overlapping YAC clones964c2, 74163, 797d11 and part of 854f5 (depicted as region A in FIG.1C). Identical alleles were observed in at least two pedigrees from thesame ethnic origin (Table 2). As part the strategy, it was reasoned thatthe presence of shared alleles at one of these groups of physicallyclustered marker loci might reflect the co-inheritance of a smallphysical region surrounding the PS1 gene on the original founderchromosome in each ethnic population. Significantly, each of the sharedextended haplotypes were rare in normal Caucasian populations and allelesharing was not observed at other groups of markers spanning similargenetic intervals elsewhere on chromosome 14q24.3.

Transcription mapping and preliminary analysis of candidate genes

To isolate expressed sequences encoded within both critical intervals, adirect selection strategy was used involving immobilized, cloned, humangenomic DNA as the hybridization target to recover transcribed sequencesfrom primary complementary DNA pools derived from human brain mRNA(Rommens et al., 1993). Approximately 900 putative cDNA fragments ofsize 100 to 600 base pairs were recovered from regions A and B in FIG.1C. These fragments were hybridized to Southern blots containing genomicDNAs from each of the overlapping YAC clones and genomic DNAs fromhumans and other mammals. This identified a subset of 151 clones whichshowed evidence for evolutionary conservation and/or for a complexstructure which suggested that they were derived from spliced mRNA. Theclones within this subset were collated on the basis of physical maplocation, cross-hybridization and nucleotide sequence, and were used toscreen conventional human brain cDNA libraries for longer cDNAs. Atleast 19 independent cDNA clones over 1 kb in length were isolated andthen aligned into a partial transcription map of the AD3 region (FIG.1D). Only three of these transcripts corresponded to known characterizedgenes (cFOS, dihydrolipoamide succinyl transferase and latenttransforming growth factor binding protein 2).

Recovery of Potential Candidate Genes

Each of the open reading frame portions of the candidate genes wererecovered by RT-PCR from mRNA isolated from post-mortem brain tissue ofnormal control subjects and from either post-mortem brain tissue orcultured fibroblast cell lines of affected members of six pedigreesdefinitively linked to chromosome 14. The RT-PCR products were thenscreened for mutations using chemical cleavage and restrictionendonuclease fingerprinting single-strand sequence conformationalpolymorphism methods (Saleeba and Cotton, 1993; Liu and Sommer, 1995),and by direct nucleotide sequencing. With one exception, all of thegenes examined, although of interest, were not unique to affectedsubjects, and did not co-segregate with the disease. The singleexception was the candidate gene represented by clone S182 whichcontained a series of nucleotide changes not observed in normalsubjects, but which altered the predicted amino acid sequence inaffected subjects. Although nucleotide sequence differences were alsoobserved in some of the other genes, most were in the 3' untranslatedregions and none were unique to AD-affected subjects.

The remaining sequences, a subset of which are mapped in FIG. 1B,together with additional putative transcriptional sequences notidentified in FIG. 1C, are identified in the sequence listings as Nos.14 to 43. The sequences identified by SEQ ID NOs: 14 to 43 representneighbouring genes or fragments of neighbouring genes adjacent to thehPS1 gene or possibly additional coding fragments arising fromalternative splicing of the hPS1. Sequences identified by SEQ ID NOs:44-126 and 150-160 represent neighboring genomic fragments containingboth exon and intron information. Such sequences are useful for creatingprimers, for creating diagnostic tests, creating altered regulatorysequences and use of adjacent genomic sequences to create better animalmodels.

Characterization of the Human PS1 (ARMP) gene

Hybridization of the S182 clone to northern blots identified atranscript expressed widely in many areas of brain and peripheraltissues as a major 3.0 kb transcript and a minor transcript of 7.0 kb.Although the identity of the ˜7.0 kb transcript is unclear, twoobservations suggest that the ˜3.0 kb transcript represents an activeproduct of the gene. Hybridization of the S182 clone to northern blotscontaining mRNA from a variety of murine tissues, including brain,identifies only a single transcript identical in size to the ˜3.0 kbhuman transcript. All of the longer cDNA clones recovered to date(2.6-2.8 kb), which include both 5' and 3' UTRs and which account forthe ˜3.0 kb band on the northern blot, have mapped exclusively to thesame physical region of chromosome 14. From these experiments the ˜7.0kb transcript could represent either a rare alternately spliced orpolyadenylated isoform of the ˜3.0 kb transcript or could representanother gene with homology to S182.

The nucleotide sequence of the major transcript was determined from theconsensus of eleven independent longer cDNA clones and from 3independent clones recovered by standard 5' rapid amplification of cDNAends and bears no significant homology to other human genes. The cDNA ofthe sequenced transcript is provided in SEQ ID NO:1 and the predictedamino acid sequence is provided in SEQ ID NO:2. The cDNA sequence ofanother sequenced human clone is also provided as SEQ ID NO:133 and itspredicted amino acid sequence is provided in SEQ ID NO:134.

Analysis of the 5' end of multiple cDNA clones and RT-PCR products aswell as corresponding genomic clones indicates that the 5' UTR iscontained within at least two exons and that transcription either beginsfrom two different start sites and/or that one of the early 5'untranslated exons is alternatively spliced (Table 6). The longestpredicted open reading frame contains 467 amino acids with a smallalternatively spliced exon of 4 amino acids at 25 codons from theputative start codon (Table 3). This putative start codon is the firstin phase ATG located 63 bp downstream of a TGA stop codon and lacks aclassical Kozak consensus sequences around the first two in-phase ATGsequences (Sherrington, 1995). Like other genes lacking classical`strong` start codons, the putative 5' UTR of the human transcripts isrich in GC.

Further investigation of the PS1 gene has revealed a host of sequencefragments which form the PS1 gene and include intron sequenceinformation, 5' end untranslated sequence information and 3' enduntranslated sequence information (Table 6). Such sequence fragments areidentified as SEQ ID NOs:6 to 13.

The DNA sequence of the PS1 gene as cloned has been incorporated into aplasmid Bluescript. This stable vector has been deposited at ATCC,Rockville, Md., under ATCC accession number 97124 on Apr. 28, 1995.

Identification of an Alternate Splice Form of the PS1 (ARMP) GeneProduct

During sequencing studies of RT-PCR products for the PS1 gene recoveredfrom a variety of tissues, it was discovered that some peripheraltissues (principally white blood cells) demonstrated two alternativesplice forms of the PS1 gene. One form is identical to the (putatively467 amino acid) isoform constitutively expressed in all brain regions.The alternative splice form results from the exclusion of the segment ofthe cDNA comprising base pairs 1018 to 1116, and results in a truncatedisoform of the PS1 protein wherein the hydrophobic part of thehydrophilic acidically-charged loop immediately C-terminal to TM6 isremoved. This alternatively spliced isoform therefore is characterizedby preservation of the sequence N-terminal to and including the tyrosineat position 256, changing of the aspartate at 257 to alanine, andsplicing on to the C-terminal part of the protein from and includingtyrosine 291. Such splicing differences are often associated withimportant functional domains of the proteins. This argues that thishydrophilic loop (and consequently the N-terminal hydrophilic loop withsimilar amino acid charge) is/are active functional domains of the PS1product and thus sites for therapeutic targeting.

Functional Domains of the PS1 (ARMP) Protein

With respect to DNA SEQ ID NO:1 and DNA SEQ ID NO:133, analysis of thesequence of overlapping cDNA clones predicted an ORF protein of 467amino acids when read from the first in phase ATG start codon, and amolecular mass of approximately 52.6 kDa. The molecular weight of theprotein can vary due to possible substitutions, insertions or deletionsof amino acids or due either to polymorphisms in the protein oralternate splicing of the transcript.

Analysis of the predicted amino acid sequence using the Hopp and Woodsalgorithm suggested that the PS1 protein product is a multispanningintegral membrane protein such as a receptor, a channel protein, or astructural membrane protein. The absence of recognizable signal peptideand the paucity of glycosylation sites are noteworthy, and thehydropathy profile suggests that the protein is less likely to be asoluble protein with a highly compact three-dimensional structure.

The protein may be a cellular protein with a highly compact threedimensional structure in which respect it may be similar to APOE whichis also related to Alzheimer's Disease. As mutations in this protein areassociated with early onset (presenile) Alzheimer's Disease, the proteinhas been designated presenilin I (PS1).

The protein also contains a number of potential phosphorylation sites,one of which is the consensus site for MAPkinase which is also involvedin the hyperphosphorylation of tau during the conversion of normal tauto neurofibrillary tangles. This consensus sequence may provide aputative common pathway linking this protein and other known biochemicalaspects of Alzheimer's Disease and would represent a likely therapeutictarget. Review of the protein structure reveals two sequences YTPF(residues 115-119) and STPE (residues 353-356) which represent the 5/T-Pmotif which is the MAP kinase consensus sequence. Several otherphosphorylation sites exist with consensus sequences for Protein KinaseC (PKC) activity. Because PKC activity is associated with differences inthe metabolism of APP which are relevant to Alzheimer's Disease, thesesites on the PS1 protein and homologues are sites for therapeutictargeting.

The N-terminal is characterized by a highly hydrophilic acidic chargeddomain with several potential phosphorylation domains, followedsequentially by a hydrophobic membrane spanning domain of 19 residues, acharged hydrophilic loop, five additional hydrophobic membrane spanningdomains interspersed with short (5-20 residue) hydrophilic domains, anadditional larger acidic hydrophilic charged loop and at least one, andpossibly two, other hydrophobic potentially membrane-spanning domains,culminating in a polar domain at the C-terminus (Table 4 and FIG. 3B).The presence of seven membrane spanning domains is characteristic ofseveral classes of G-coupled receptor proteins but is also observed withother proteins including channel proteins.

PS1 (ARMP) Protein

The PS1 (ARMP) protein is a member of a novel class of transmembraneproteins which share substantial amino acid homology. The homology issufficient that certain nucleotide probes and antibodies raised againstone can identify other members of this gene family. The majordifferences between members of this family reside in the amino acid andnucleotide sequence homologous to the hydrophilic acid loop domainbetween putative transmembrane 6 and transmembrane 7 domains of the PS1gene and gene product. This region is alternatively spliced in somenon-neural tissues, and is also the site of several pathogenicdisease-causing mutations in the PS1 gene. The variable splicing of thishydrophilic loop, the presence of a high density of pathogenic mutationswithin this loop, and the fact that the amino acid sequences of the loopdiffers between members of the gene family suggest that this loop is animportant functional domain of the protein and may confer somespecificity to the physiologic and pathogenic interactions which the PS1gene product undergoes. Because the N-terminal hydrophilic domain sharesthe same acidic charge as the hydrophilic acid loop domain between TM6and TM7, and has the same orientation with respect to the membrane, itis very likely that these two domains share functionality either in acoordinated (together) or independent fashion (e.g. different ligands orfunctional properties). As a result everything said about thehydrophilic loop applies also to the N-terminal hydrophilic domain.

Knowledge of the specificity of the loop can be used to identify ligandsand functional properties of the PS1 gene product (e.g. sites ofinteractions with APP, cytosolic proteins such as kinases, Tau, and MAP,etc.).

Comparison of the nucleic acid and predicted amino acid sequences of PS1with available databases using the BLAST alignment paradigms revealedmodest amino acid similarity with the C. elegans sperm integral membraneprotein SPE-4 (p=1.5e⁻²⁵, 24-37% identity over three groups of at leastfifty residues) and weaker similarity to portions of several othermembrane spanning proteins including mammalian chromogranin A and thealpha subunit of mammalian voltage dependent calcium channels (Altschulet al., 1990). This clearly established that they are not the same gene.The amino-acid sequence similarities across putative transmembranedomains may occasionally yield alignment that simply arises from thelimited number of hydrophobic amino acids, but there is also extendedsequence alignment between S182 protein and SPE-4 at several hydrophilicdomains. Both the putative PS1 protein and SPE-4 are predicted to be ofcomparable size (467 and 465 residues, respectively) and to contain atleast seven transmembrane domains with a large acidic domain precedingthe final predicted transmembrane domain. The PS1 protein does have alonger predicted hydrophilic region at the N terminus.

The similarity between the putative products of the SPE-4 and PS1 genesimplies that they may have similar activities. The SPE-4 protein of C.elegans appears to be involved in the formation and stabilization of thefibrous body-membrane organelle (FBMO) complex during spermatogenesis.The FBMO is a specialized Golgi-derived organelle, consisting of amembrane bound vesicle attached to and partly surrounding a complex ofparallel protein fibers and may be involved in the transport and storageof soluble and membrane-bound polypeptides. Mutations in SPE-4 disruptthe FBMO complexes and arrest spermatogenesis. Therefore the physiologicfunction of SPE-4 may be either to stabilize interactions betweenintegral membrane budding and fusion events, or to stabilizeinteractions between the membrane and fibrillary proteins during theintracellular transport of the FBMO complex during spermatogenesis.Comparable functions could be envisaged for PS1. The PS1 could beinvolved either in the docking of other membrane-bound proteins such asβAPP, or the axonal transport and fusion budding of membrane-boundvesicles during protein transport such as in the Golgi apparatus orendosome-lysosome system. If correct, then mutations might be expectedto result in aberrant transport and processing of βAPP and/or abnormalinteractions with cytoskeletal proteins such as themicrotubule-associated protein Tau. Abnormalities in the intracellularand in the extracellular disposition of both βAPP and Tau are in fact anintegral part of the neuropathologic features of Alzheimer's Disease.Although the location of the PS1 mutations in highly conserved residueswithin conserved domains of the putative proteins suggests that they arepathogenic, at least three of these mutations are conservative which iscommensurate with the onset of disease in adult life. Because none ofthe mutations observed so far are deletions or nonsense mutations thatwould be expected to cause a loss of function, we cannot predict whetherthese mutations will have a dominant gain-of-function effect and promoteaberrant processing of βAPP or a dominant loss-of-function effectcausing arrest of normal βAPP processing.

An alternate possibility is that the ARMP gene product may represent areceptor or channel protein. Mutations of such proteins have beencausally related to several other dominant neurological disorders inboth vertebrate (e.g., malignant hyperthermia, hyperkalemic periodicparalysis in humans) and in invertebrate organisms (deg-1(d) mutants inC.elegans). Although the pathology of these other disorders does notresemble that of Alzheimer's Disease there is evidence for functionalabnormalities in ion channels in Alzheimer's Disease. For example,anomalies have been reported in the tetra-ethylammonium-sensitive 113pSpotassium channel and in calcium homeostasis. Perturbations intransmembrane calcium fluxes might be especially relevant in view of theweak homology between PS1 and the α-ID subunit of voltage-dependentcalcium channels and the observation that increases in intracellularcalcium in cultured cells can replicate some of the biochemical featuresof Alzheimer's Disease such as alteration in the phosphorylation ofTau-microtubule-associated protein and increased production of Aβpeptides.

The normal PS1 protein, substantially free of other proteins, is encodedby the aforementioned SEQ. ID No:1 and SEQ ID NO:133. As will be laterdiscussed, PS1 protein and fragments thereof may be made by a variety ofmethods. Purified mutant PS1 protein is characterized by FAD--associatedphenotype (necrotic death, apoptotic death, granulovasculardegeneration, neurofibrillary degeneration, abnormalities or changes inthe metabolism of APP, Ca²⁺, K⁺, and glucose, mitochondrial function andenergy metabolism neurotransmitter metabolism, all of which have beenfound to be abnormal in human brain, and/or peripheral tissue cells insubjects with Alzheimer's Disease) in a variety of cells. The mutantPS1, free of other proteins, is encoded by the mutant DNA sequence.

Mutations in the S182 (PS1) transcript

Several mutations in the ARMP gene have been identified which cause asevere type of familial Alzheimer's Disease. One or a combination ofthese mutations may be responsible for this form of Alzheimer's Diseaseas well as several other neurological disorders. The mutations may beany form of nucleotide sequence alteration or substitution. Specificdisease causing mutations in the form of nucleotide and/or amino acidsubstitutions have been located, although it is anticipated thatadditional mutations will be found in other families.

Direct sequencing of overlapping RT-PCR products spanning the 3.0 kbS182 transcript isolated from affected members of the six largepedigrees linked to chromosome 14 led to the discovery of eight missensemutations in each of the six pedigrees (Table 7, FIG. 2). Each of thesemutations co-segregated with the disease in the respective pedigrees,and were absent from upwards of 142 unrelated neurologically normalsubjects drawn from the same ethnic origins as the FAD pedigrees (284unrelated chromosomes).

The location of the gene within the physical interval segregating withAD3 trait, the presence of eight different missense mutations whichco-segregate with the disease trait in six pedigrees definitively linkedto chromosome 14, and the absence of these mutations in 284 independentnormal chromosomes cumulatively confirms that the PS1 gene is the AD3locus. Further biologic support for this hypothesis arises both from thefact that the residues mutated in FAD kindreds are conserved inevolution (Table 3) and occur in domains of the protein which are alsohighly conserved, and from the fact that the PS1 gene product isexpressed at high levels in most regions of the brain including thosemost severely affected by AD.

Each of the observed nucleotide substitutions occurred within theputative ORF of the PS1 transcript, and would be predicted to change theencoded amino acid at the following positions, numbering from the firstputative initiation codon. The mutations are listed both with referenceto their nucleotide locations in SEQ ID NO:1 and SEQ ID NO:133 (anadditional human clone) and to their amino acid locations in SEQ ID NO:2and SEQ ID NO:134 (the additional human clone).

    ______________________________________                                        i)        686, A→C                                                                        Met         146  Leu                                       ii)       737, A→G                                                                        His         163  Arg                                       iii)      986, C→A                                                                        Ala         246  Glu                                       iv)      1105, C→G                                                                        Leu         286  Val                                       v)       1478, G→A                                                                        Cys         410  Tyr                                       vi)      1027, C→T                                                                        Ala         260  Val                                       vii)     1102, C→T                                                                        Ala         285  Val                                       viii)    1422, C→G                                                                        Leu         392  Val                                       ______________________________________                                    

A further missense mutation was found in presenilin I:

    ______________________________________                                        Leu    171    Pro                                                             ______________________________________                                    

The Met146Leu, Ala246Glu and Cys410Tyr mutations have not been detectedin the genomic DNA of affected members of the eight remaining smallearly onset autosomal dominant FAD pedigrees or six additional familiesin our collection which express late PAD onset. We predict that suchmutations would not commonly occur in late onset FAD which has beenexcluded by genetic linkage studies from the more aggressive form of ADlinked to chromosome 14q24.3 (St George-Hyslop, P et al., 1992;Schellenberg et al., 1993). The His163Arg mutation has been found in thegenomic DNA of affected members of one additional FAD pedigree for whichpositive but significant statistical evidence for linkage to 14 becomesestablished. Age of onset of affected members was consistent withaffected individuals from families linked to chromosome 14.

Mutations Ala260Val, Ala285Val, and Leu392Val all occur within theacidic hydrophilic loop between putative transmembrane domain 6 (TM6)and transmembrane domain 7 (TM7) (FIG. 3). Two of these mutations(A260V; A285V) and the L286V mutation are also located in the alternatesplice domain.

All nine mutations can be assayed by a variety of strategies (directnucleotide sequencing, allele specific oligos, ligation polymerase chainreaction, SSCP, RFLPs etc.) using RT-PCR products representing themature mRNA/cDNA sequence or genomic DNA.

Of all the nucleotide substitutions co-segregating with the disease intheir respective pedigrees, none were seen in asymptomatic familymembers aged more than two standard deviations beyond the mean age ofonset, and none were present on 284 chromosomes from unrelatedneurologically normal subjects drawn from comparable ethnic origins.

Table 9 shows the above-noted PS1 mutations and other publishedmutations of this gene.

Isolation and Purification of PS1 (ARMP) Protein

The PS1 protein may be isolated and purified by methods selected on thebasis of properties revealed by its sequence. Since the proteinpossesses properties of a membrane-spanning protein, a membrane fractionof cells in which the protein is highly expressed (e.g. central nervoussystem cells or cells from other tissues) is isolated and the proteinsextracted by detergent solubilization.

Purification can be achieved using protein purification procedures suchas chromatography methods (gel-filtration, ion-exchange andimmunoaffinity), by high-performance liquid chromatography (RP-HPLC,ion-exchange HPLC, size-exclusion HPLC, high-performancechromatofocusing and hydrophobic interaction chromatography) or byprecipitation (immunoprecipitation). Polyacrylamide gel electrophoresiscan also be used to isolate the PS1 protein based on its molecularweight, charge properties and hydrophobicity.

Similar procedures to those just mentioned could be used to purify theprotein from cells transfected with vectors containing the PS1 gene(e.g. baculovirus systems, yeast expression systems, eukaryoticexpression systems).

Purified protein can be used in further biochemical analyses toestablish secondary and tertiary structure which may aid in the designof pharmaceuticals to interact with the protein, alter protein chargeconfiguration or charge interaction with other proteins, lipid orsaccharide moieties, alter its function in membranes as a transporterchannel or receptor and/or in cells as an enzyme or structural proteinand treat the disease.

The protein can also be purified by creating a fusion protein byligating the PS1 cDNA sequence to a vector which contains a sequence foranother peptide (e.g. GST--glutathione succinyl transferase). The fusionprotein is expressed and recovered from prokaryotic (e.g. bacterial orbaculovirus) or eukaryotic cells. The fusion protein can then bepurified by affinity chromatography based upon the fusion vectorsequence. The PS1 protein can then be further purified from the fusionprotein by enzymatic cleavage of the fusion protein.

Expression of PS1 (ARMP)

As an embodiment of the present invention, PS1 protein may be expressedusing eukaryotic and prokaryotic expression systems. Eukaryoticexpression systems can be used for many studies of the PS1 gene and geneproduct including determination of proper expression andpost-translational modifications for full biological activity,identifying regulatory elements located in the 5' region of the PS1 geneand their role in tissue regulation of protein expression, andproduction of large amounts of the normal and mutant protein forisolation and purification. Cells expressing the PS1 protein may be usedas a functional assay system for antibodies generated against theprotein or to test effectiveness of pharmacological agents. Expressedand purified PS1 protein may be used to examine its role as a componentof a signal transduction system and to study the function of the normalcomplete protein, specific portions of the protein, or of naturallyoccurring and artificially produced mutant proteins.

Prokaryotic expression systems allow the holo-protein, or variousimportant functional domains of the protein, to be recovered as fusionproteins and used for binding studies, structural studies, functionalstudies, and for the generation of appropriate antibodies.

Expression of the PS1 gene in heterologous cell systems can be used todemonstrate structure-function relationships. Ligating the PS1 DNAsequence into a plasmid expression vector to transfect cells is a usefulmethod to test the influence of PS1 on various cellular biochemicalparameters. Plasmid expression vectors containing either the entirenormal or mutant human or mouse PS1 sequence or portions thereof, can beused in in vitro mutagenesis experiments which will identify portions ofthe protein crucial for regulatory function.

The DNA sequence can be manipulated in studies to understand theexpression of the gene and its product, to achieve production of largequantities of the protein for functional analysis, for antibodyproduction, and for patient therapy. Changes in the sequence may or maynot alter the expression pattern in terms of relative quantities,tissue-specificity and functional properties. Partial or full-length DNAsequences which encode for the PS1 protein, modified or unmodified, maybe ligated to bacterial expression vectors. E. coli can be used with avariety of expression vector systems, e.g. the T7 RNApolymerase/promoter system using two plasmids or by labelling ofplasmid-encoded proteins, or by expression by infection with M13 PhagemGPI-2. E. coli vectors can also be used with Phage lambda regulatorysequences, by fusion protein vectors (e.g. lacZ and trpE), bymaltose-binding protein fusions, and by glutathione-S-transferase fusionproteins, etc., all of which, together with many other prokaryoticexpression systems, are widely available commercially.

Alternatively, the PS1 protein can be expressed in insect cells usingbaculoviral vectors, or in mammalian cells using vaccinia virus orspecialised eukaryotic expression vectors. For expression in mammaliancells, the cDNA sequence may be ligated to heterologous promoters, suchas the simian virus (SV40) promoter in the pSV2 vector or other similarvectors and introduced into cultured eukaryotic cells such as COS cellsto achieve transient or long-term expression. The stable integration ofthe chimeric gene construct may be maintained in mammalian cells bybiochemical selection, such as neomycin and mycophoenolic acid.

The PS1 DNA sequence can be altered using procedures such as restrictionenzyme digestion, fill-in with DNA polymerase, deletion by exonuclease,extension by terminal deoxynucleotide transferase, ligation of syntheticor cloned DNA sequences and site-directed sequence alteration with theuse of specific oligonucleotides together with PCR.

The cDNA sequence or portions thereof, or a mini gene consisting of acDNA with an intron and its own promoter, is introduced into eukaryoticexpression vectors by conventional techniques. These vectors permit thetranscription of the cDNA in eukaryotic cells by providing regulatorysequences that initiate and enhance the transcription of the cDNA andensure its proper splicing and polyadenylation. The endogenous PS1 genepromoter can also be used. Different promoters within vectors havedifferent activities which alters the level of expression of the cDNA.In addition, certain promoters can also modulate function such as theglucocorticoid-responsive promoter from the mouse mammary tumor virus.

Some of the vectors listed contain selectable markers or neo bacterialgenes that permit isolation of cells by chemical selection. Stablelong-term vectors can be maintained in cells as episomal, freelyreplicating entities by using regulatory elements of viruses. Cell linescan also be produced which have integrated the vector into the genomicDNA. In this manner, the gene product is produced on a continuous basis.

Vectors are introduced into recipient cells by various methods includingcalcium phosphate, strontium phosphate, electroporation, lipofection,DEAE dextran, microinjection, or by protoplast fusion. Alternatively,the cDNA can be introduced by infection using viral vectors.

Using the techniques mentioned, the expression vectors containing thePS1 gene or portions thereof can be introduced into a variety ofmammalian cells from other species or into non-mammalian cells asdescribed in Example 8.

The recombinant expression vector, according to this invention,comprises the selected DNA of the DNA sequences of this invention forexpression in a suitable host. The DNA is operatively joined in thevector to an expression control sequence in the recombinant DNA moleculeso that normal or mutant PS1 protein can be expressed. The expressioncontrol sequence may be selected from the group consisting of sequencesthat control the expression of genes of prokaryotic or eukaryotic cellsand their viruses and combinations thereof. The expression controlsequence may be selected from the group consisting of the lac system,the trp system, the tac system, the trc system, major operator andpromoter regions of phage lambda, the control region of the fd coatprotein, early and late promoters of SV40, promoters derived frompolyoma, adenovirus, retrovirus, baculovirus, simian virus,3-phosphoglycerate kinase promoter, yeast acid phosphatase promoters,yeast alpha-mating factors and combinations thereof.

The host cells to be transfected with the vectors of this invention maybe from a host selected from the group consisting of E. coli,Pseudomonas, Bacillus subtillus, Bacillus stearothermophilus, or otherbacilli, other bacteria, yeasts, fungi, insects, mice or other animalsor plant hosts or may be human tissue cells.

For the mutant PS1 DNA sequence, similar systems are employed to expressand produce the mutant protein.

Antibodies to PS1 (ARMP)

Antibodies to epitopes within the PS1 protein can be raised to provideinformation on the characteristics of the proteins. Generation ofantibodies enables the visualization of the protein in cells and tissuesusing Western blotting. In this technique, proteins are separated bypolyacrylamide gel electrophoresis and transferred to nitrocellulosemembranes. These membranes are then incubated in the presence of aprimary antibody, washed and incubated with a secondary antibody todetect the protein-primary antibody complex. Following repeated washing,the entire complex is visualized using colourimetric or chemiluminescentmethods.

Antibodies to the PS1 protein also allow for the use ofimmunocytochemistry and immunofluorescence techniques in which theproteins can be visualized directly in cells and tissues. This is mosthelpful in order to establish the subcellular location of the proteinand the tissue specificity of the protein.

In order to prepare polyclonal antibodies, fusion proteins containingdefined portions or all of the PS1 protein may be synthesized inbacteria by expression of corresponding DNA sequences in a suitablecloning vehicle, as described herein. The protein is then purified,coupled to a carrier protein, mixed with Freund's adjuvant (to helpstimulate the antigenic response) and injected into rabbits or othersuitable animals. Alternatively, protein can be isolated from culturedcells expressing the protein. Following booster injections at bi-weeklyintervals, the rabbits or other suitable animals are bled and the seraisolated. Sera are used directly or purified prior to use, by variousmethods including affinity chromatography, Protein A-Sepharose, AntigenSepharose, Anti-mouse-Ig-Sepharose. Sera or purified antibodies are usedto probe protein extracts run on a polyacrylamide gel to identify thePS1 protein. Alternatively, antibodies may be obtained by makingsynthetic peptides corresponding to antigenic portions of the PS1protein and injecting these into rabbits or other suitable animals.

To produce monoclonal PS1 antibodies, cells actively expressing theprotein are cultured or isolated from tissues and the cell membranesisolated. The membranes, extracts, or recombinant protein extractscontaining the PS1 protein are injected in Freund's adjuvant into mice.After receiving 9 injections over a three week period, the mice aresacrificed and their spleens are removed and resuspended in phosphatebuffered saline (PBS). The spleen cells serve as a source oflymphocytes, some of which are producing antibody of the appropriatespecificity. These cells are then fused with a permanently growingmyeloma partner cell, and the products of the fusion are plated into anumber of tissue culture wells in the presence of a selective agent suchas HAT. The wells are screened by ELISA to identify those containingcells making useful antibody and these cells are freshly plated. After aperiod of growth, these cells are again screened to identifyantibody-producing cells. Several cloning procedures are carried outuntil over 90% of the wells contain single clones which are positive forantibody production. By this procedure, a stable line of monoclonalantibody-producing clones is established. Monoclonal antibody producedby such clones is purified by methods such as affinity chromatographyusing Protein A Sepharose or ion-exchange chromatography or byvariations and combinations of these techniques.

Antibodies may also be used coupled to other compounds or materials fordiagnostic and/or therapeutic uses. For example, they may be coupled toradionuclides for imaging and therapy, or to liposomes for the targetingof compounds contained in the liposomes to a specific tissue location.

Isolation of Murine PS1 gene

In order to characterize the physiological significance of the normaland mutant human PS1 gene and gene products in a transgenic mouse model,it was necessary to recover a mouse homologue of the human PS1 gene. Amurine homologue of the human PS1 gene was recovered by screening amouse cDNA library with a labelled human DNA probe. In this manner, a 2kb partial transcript (representing the 3' end of the gene) and severalRT-PCR products representing the 5' end were recovered. Sequencing ofthe consensus cDNA transcript of the murine homologue revealedsubstantial amino acid identity. The mouse cDNA sequence is identifiedas SEQ ID NO:3 and the predicted amino acid sequence is identified asSEQ ID NO:4. Further sequencing of the mouse cDNA transcript hasprovided the complete coding sequence, identified as SEQ ID NO:135. Moreimportantly, all of the amino acids that were mutated in the FADpedigrees were conserved between the murine homologue and the normalhuman variant (Table 3). This conservation of the PS1 gene, as is shownin Table 3, indicates that an orthologous gene exists in the mouse(mPS1), and it is now possible to clone mouse genomic libraries usinghuman PS1 probes. This will also make it possible to identify andcharacterize the PS1 gene in other species. This also provides evidenceof animals with various disease states or disorders currently known oryet to be elucidated.

Transgenic Mouse Model

The creation of a mouse model for Alzheimer's Disease is important tothe understanding of the disease and for the testing of possibletherapies. Currently no unambiguous viable animal model for Alzheimer'sDisease exists.

There are several ways in which to create an animal model forAlzheimer's Disease. One strategy is the generation, in the mouse gene,of a specific mutation such as one of the identified human PS1 genemutations. Secondly, a wild type human gene could be inserted and/or themurine gene could be humanized by homologous recombination. Thirdly, itis possible to insert a mutant (single or multiple) human gene as agenomic or minigene cDNA construct using wild type, mutant or artificialpromoter elements. Fourthly, knock-out of the endogenous murine genesmay be accomplished by the insertion of artificially modified fragmentsof the endogenous gene by homologous recombination. The modificationsinclude insertion of mutant stop codons, the deletion of DNA sequences,or the inclusion of recombination elements (lox p sites) recognized byenzymes such as Cre recombinase.

To inactivate the mPS1 gene, chemical or x-ray mutagenesis of mousegametes, followed by fertilization, can be applied. Heterozygousoffspring may be identified by Southern blotting to demonstrate loss ofone allele by dosage, or failure to inherit one parental allele usingRFLP markers.

To create a transgenic mouse, a mutant version of PS1 or mPS1 can beinserted into a mouse germ line using standard techniques of oocytemicroinjection, or transfection or microinjection into stem cells.Alternatively, if it is desired to inactivate or replace the endogenousmPS1 gene, homologous recombination using embryonic stem cells may beapplied.

For oocyte injection, one or more copies of the mutant or wild type PS1gene can be inserted into the pronucleus of a just-fertilized mouseoocyte. This oocyte is then reimplanted into a pseudo-pregnant fostermother. The liveborn mice are screened for integrants using analysis oftail DNA for the presence of human PS1 gene sequences. The transgene maybe either a complete genomic sequence injected as a YAC, BAC, PAC orother chromosome DNA fragment, a cDNA with either the natural promoteror a heterologous promoter, or a minigene containing all of the codingregion and other elements found to be necessary for optimum expression.

Retroviral infection of early embryos can also be done to insert themutant or wild type human PS1. In this method, the mutant or wild typePS1 is inserted into a retroviral vector which is used to infect mouseembryos directly during the early stages of development to generatechimeras, some of which will lead to germline transmission. Similarexperiments can be conducted in the case of mutant proteins, usingmutant murine or other animal PS1 gene sequences.

Homologous recombination using stem cells allows for the screening ofgene transfer cells to identify the rare homologous recombinationevents. Once identified, these can be used to generate chimeras byinjection of mouse blastocysts, and a proportion of the resulting micewill show germline transmission from the recombinant line. Thismethodology is especially useful if inactivation of the mPS1 gene isdesired. For example, inactivation of the mPS1 gene can be done bydesigning a DNA fragment which contains sequences from a mPS1 exonflanking a selectable marker. Homologous recombination leads to theinsertion of the marker sequences in the middle of an exon, inactivatingthe mPS1 gene. DNA analysis of individual clones can then be used torecognize the homologous recombination events.

It is also possible to create mutations in the mouse germline byinjecting oligonucleotides containing the mutation of interest andscreening the resulting cells by PCR.

This embodiment of the invention has the most significant commercialvalue as a mouse model for Alzheimer's Disease. Because of the highpercentage of sequence conservation between human and mouse it iscontemplated that an orthologous gene will exist also in many otherspecies. It is thus contemplated that it will be possible to generateother animal models using similar technology.

Isolation of the Human PS2 (E5-1) gene, a homologue of the PS1 (ARMP)gene

A gene, presenilin II (PS2) or E5-1, with substantial nucleotide andamino acid homology to the PS1 gene was identified by using thenucleotide sequence of the cDNA for PS1 to search data bases using theBLASTN paradigm of Altschul et al. 1990. Three expressed sequence taggedsites (ESTs) identified by accession numbers T03796, R14600, and R05907were located which had substantial homology (p<1.0 e⁻¹⁰⁰, greater than97% identity over at least 100 contiguous base pairs).

Oligonucleotide primers were produced from these sequences and used togenerate PCR products by reverse transcriptase PCR (RT-PCR). These shortRT-PCR products were partially sequenced to confirm their identity withthe sequences within the data base and were then used as hybridizationprobes to screen full-length cDNA libraries. Several different cDNA'sranging in size from 1 Kb to 2.3 Kb were recovered from a cancer cellcDNA library (CaCo-2) and from a human brain cDNA library (E5-1, G1-1,cc54, cc32).

The nucleotide sequence of these clones confirmed that all werederivatives of the same transcript.

The gene encoding the transcript, the PS2 gene, mapped to humanchromosome 1 using hybrid mapping panels and to two clusters of CEPHMega YAC clones which have been placed upon a physical contig map (YACclones 750g7, 921d12 mapped by FISH to 1q41; and YAC clone 787g12 whichalso contains an EST for the leukemia associated phosphoprotein (LAP18)gene which has been mapped to 1p36.1-p35) (data not shown).

Hybridization of the (E5-1) PS2 cDNA clones to Northern Blots detectedan ˜2.3 kilobase mRNA band in many tissues including regions of thebrain, as well as a ˜2.6Kb mRNA band in muscle, cardiac muscle andpancreas.

In skeletal muscle, cardiac muscle and pancreas, the (E5-1) PS2 gene isexpressed at relatively higher levels than in brain and as two differenttranscripts of ˜2.3 Kb and ˜2.6 Kb. Both of the transcripts have sizesclearly distinguishable from that of the 2.7 Kb PS1 transcript, and didnot cross-hybridize with PS1 probes at high stringency. The cDNAsequence of the (E5-1) PS2 gene is identified as SEQ ID NO:136.

The longest ORF within the (E5-1) PS2 cDNA consensus nucleotide sequencepredicts a polypeptide containing 448 amino acids (SEQ ID NO:137)numbering from the first in-phase ATG codon which was surrounded by aGCC-agg-GCt-ATG-c Kozak consensus sequence.

Analysis of RT-PCR products from brain and muscle RNA revealed thatnucleotides 1153-1250 of the PS2 transcript are alternately spliced.

A splice variant of the (E5-1) PS2 cDNA sequence identified as SEQ IDNO:136 has also been found in all tissues examined. This splice variantlacks the triplet GAA at nucleotide positions 1338-1340.

A further variant has been found in one normal individual whose (E5-1)PS2 cDNA had C replacing T at nucleotide position 626, without anychange in the amino acid sequence.

The DNA sequence of the PS2 gene as cloned has been incorporated into avector and deposited at ATCC, Rockville, Md., under ATCC accessionnumber 97214 on Jun. 28, 1995.

Mutations of the PS2 (E5-1) gene associated with Alzheimer's Disease

The strong similarity between PS1 and the (E5-1) PS2 gene product raisedthe possibility that the (E5-1) PS2 gene might be the site ofdisease-causing mutations in some of a small number of early onset ADpedigrees in which genetic linkage studies have excluded chromosomes 14,19 and 21. RT-PCR was used to isolate cDNAs corresponding to the (E5-1)PS2 transcript from lymphoblasts, fibroblasts or post-mortem braintissue of affected members of eight pedigrees with early onset FAD inwhich mutations in the βAPP and PS1 gene had previously been excluded bydirect sequencing studies.

Examination of these RT-PCR products detected a heterozygous A→Gsubstitution at nucleotide 1080 in all four affected members of anextended pedigree of Italian origin (Flo10) with early onset,pathologically confirmed FAD (onset=50-70 yrs). This mutation would bepredicted to cause a Met→Val missense mutation at codon 239 (Table 8).

A second mutation (A→T at nucleotide 787) causing a Asn→Ile substitutionat codon 141 was found in affected members of a group of relatedpedigrees of Volga German ancestry (represented by cell lines AG09369,AG09907, AG09952, and AG09905, Coriell Institute, Camden N.J.).Significantly, one subject (AG09907) was homozygous for this mutation,an observation compatible with the in-bred nature of these pedigrees.Significantly, this subject did not have a significantly differentclinical picture from those subjects heterozygous for the Arg141Ilemutation. Neither of the (E5-1) PS2 gene mutations were found in 284normal Caucasian controls nor were they present in affected members ofpedigrees with the AD3 type of AD.

Both of these PS2 mutations would be predicted to cause substitution ofresidues which are highly conserved within the PS1/PS2 gene family.

An additional (E5-1) PS2 mutation is caused by a T to C substitution atbase pair 1624 causing an Ile to Thr substitution at codon 420. Thismutation was found in a further case of early onset (45 years of age)familial AD.

The finding of a gene whose product is predicted to share substantialamino acid and structural similarities with the PS1 gene productsuggests that these proteins may be functionally related as independentproteins with overlapping functions but perhaps with slightly differentspecific activities, as physically associated subunits of a multimericpolypeptide or as independent proteins performing consecutive functionsin the same pathway.

The observation of three different missense mutations in conserveddomains of the (E5-1) PS2 protein in subjects with a familial form of ADargues that these mutations are, like those in the PS1 gene, causal toAD. This conclusion is significant because, while the disease phenotypeassociated with mutations in the PS1 gene (onset 30-50 yrs, duration 10years) is subtly different from that associated with mutations in the(E5-1) PS2 gene (onset 40-70 years; duration up to 20yrs), the generalsimilarities clearly argue that the biochemical pathway subsumed bymembers of this gene family is central to the genesis of at least earlyonset AD. The subtle differences in disease phenotype may reflect alower level of expression of the (E5-1) PS2 transcript in the CNS, ormay reflect a different role for the (E5-1) PS2 gene product.

By analogy to the effects of PS1 mutations, (E5-1) PS2 when mutated maycause aberrant processing of APP (Amyloid Precursor Protein) into Aβpeptide, hyperphosphorylation of Tau microtubule associated protein andabnormalities of intracellular calcium homeostasis. Interference withthese anomalous interactions provides a potential therapy for AD.

PS2 (E5-1) Protein

A comparison of the amino acid sequences of human PS1 and (E5-1) PS2homologue protein is shown in Table 8. Identical residues are indicatedby vertical lines. The locations of mutations in the (E5-1) PS2 gene areindicated by downward pointing arrows. The locations of the mutations inthe human PS1 gene are indicated by upward pointing arrows. Putative TMdomains are in open ended boxes. The alternatively spliced exons aredenoted by superscripted (E5-1) PS2 or subscripted (PS1) "*".

BLASTP alignment analyses also detected significant homology with SPE4of C. elegans (P=3.5e-26; identity=20-63% over five domains of at least22 residues), and weak homologies to brain sodium channels (alpha IIIsubunit) and to the alpha subunit of voltage dependent calcium channelsfrom a variety of species (P=0.02; identities 20-28% over two or moredomains each of at least 35 residues) (Altschul, 1990). These alignmentsare similar to those described above for the PS1 gene. However, the moststriking homology to the PS2 protein was found with the amino acidsequence predicted for PS1. PS1 and PS2 proteins share 63% overall aminoacid sequence identity, and several domains display virtually completeidentity (Table 8). Furthermore, all eight residues mutated in PS1 insubjects with AD3 are conserved in the PS2 protein (Table 8). As wouldbe expected, hydrophobicity analyses suggest that both proteins alsoshare a similar structural organization.

The similarity was greatest in several domains of the proteincorresponding to the intervals between transmembrane domain 1 (TM1) andTM6, and from TM7 to the C-terminus of the PS1 gene. The main differencefrom PS1 is a difference in the size and amino acid sequence of theacidically-charged hydrophilic loop in the position equivalent to thehydrophilic loop between transmembrane domains TM6 and TM7 in the PS1protein and in the sequence of the N-terminal hydrophilic domains.

Thus, both proteins are predicted to possess seven hydrophobic putativetransmembrane domains, and both proteins bear large acidic hydrophilicdomains at the N-terminus and between TM6 and TM7 (FIGS. 6 and 8). Afurther similarity arose from the above-described analysis of RT-PCRproducts from brain and muscle RNA, which revealed that nucleotides1153-1250 of the (E5-1) PS2 transcript are alternatively spliced. Thesenucleotides encode amino acids 263-296, which are located within theTM6-TM7 loop domain of the putative PS2 protein and which share 94%sequence identity with the alternatively spliced amino acids 257-290 inPS1.

The most noticeable differences between the two predicted amino acidsequences occur in the amino acid sequence in the central portion of theTM6→TM7 hydrophilic loop (residues 304-374 of PS1; 310-355 of (PS2), andin the N-terminal hydrophilic domain (Table 8). By analogy, this domainis also less highly conserved between the murine and human PS1 genes(identity=47/60 residues), and shows no similarity to the equivalentregion of SPE4.

Isolation and Purification of PS2 (ARMP) protein

The PS2 protein may be isolated and purified by the types of methodsdescribed above for the PS1 protein.

The protein may also be prepared by expression of the (E5-1) PS2 cDNAdescribed herein in a suitable host. The protein is preferably expressedas a fusion protein by ligating its encoding cDNA sequence to a vectorcontaining the coding sequence for another suitable peptide, e.g., GST.The fusion protein is expressed and recovered from prokaryotic cellssuch as bacterial or baculovirus cells or from eukaryotic cells.Antibodies to PS1, by virtue of portions of amino acid sequence identitywith PS2, can be used to purify, attract and bind to PS2 protein andvice versa.

Antibodies to PS2 (E5-1)

Due to its structural similarity with the PS1, the PS2 protein may beused for the development of probes, peptides, or antibodies to variouspeptides within it which may recognize both the PS2 and the PS1 geneproducts. As a protein homologue for the PS1, the PS2 protein may beused as a replacement for a defective PS1 gene product. It may also beused to elucidate functions of the PS1 gene in tissue culture and viceversa.

Transgenic Mouse Model of PS2 (E5-1)-related Alzheimer's Disease

An animal model of Alzheimer's Disease related to mutations of the PS2gene may be created by methods analogous to those described above forthe PS1 gene.

Functional Domains of Presenilins

The mutations in presenilin I (PS1) and presenilin II (PS2) clusteraround two domains, suggesting that these domains are the functionaldomains of these proteins. Five PS1 mutations cluster in the regionbetween codon 82 and codon 146 which comprises the putative firsttransmembrane domain (TM1), the TM1-TM2 loop, and the TM2 domain inpresenilin I; the mutation at codon 141 of PS2 is located in the TM2domain of presenilin II. These mutations probably destabilize theTM1-TM2 loop domain and its anchor points in TM1 and TM2. Eight PS1mutations result in the alteration of amino acids between codons 246 and410, which are involved in TM6, the TM6-TM7 loop, and TM7. The TM6-TM7loop is located on the opposite face of the membrane from the TM1-TM2loop. These mutations may modify the structure or stability of theTM6-TM7 loop (either directly or by modifying the conformation of TM6 orTM7). Further evidence for a functional domain residing in the TM6-TM7loop (amino acids 300 to 371) is the sequence divergence in the centralpart of the TM6-TM7 loop among different members of the presenilinprotein family. Because the amino-terminus sequences of members of thepresenilin protein family are divergent, it is likely that theamino-terminus, like the TM6-TM7 loop, plays a role in conferringspecificity to the function of each of the different presenilinproteins. These regions may represent ligand binding sites. If this isso, mutations in the TM6-TM7 region are likely to modify ligand bindingactivity. The TM1-TM2 loop, which is conserved amongst different membersof the presenilin protein family, probably represents an effector domainon the opposing membrane face. Both the TM6-TM7 loop and the TM1-TM2loop can be used as sites to develop specific binding agents to inhibitthe effects of the mutations and/or restore the normal function of thepresenilin protein in subjects with Alzheimer's Disease.

Isolation of Presenilin Binding Proteins

Isolation of interacting partners of the presenilins allowsidentification of the biochemical partners for the presenilins and thusthe identification of the biochemical pathway disturbed by mutations inPS1 and PS2. Such partners could be for example, enzymes, co-receptors,ligands or stabilizers. By analysing these interactions, it is possibleto design compounds which counteract the effect of the mutationinteraction, thus providing treatment for abnormal interactions. Thesetreatments might alter the interaction of the presenilins with thesepartners, they may alter the function of the interacting protein, theymay alter the amount or tissue distribution or expression of theinteraction partners, or they may alter similar properties of thepresenilins themselves.

Soluble recombinant fusion proteins can be made, or the nucleotidesequence coding for amino acids within the loop or parts of the loop canbe expressed, in suitable vectors (yeast-2-hybrid, baculovirus, andphage--display systems for instance) and used to identify other proteinswhich interact with PS1 or PS2 in the pathogenesis of Alzheimer'sDisease and other neurological and psychiatric diseases. Therapies canbe designed to modulate these interactions and thus to modulateAlzheimer's Disease and the other conditions associated with acquired orinherited abnormalities of the PS1 or PS2 genes or their gene products.The potential efficacy of these therapies can be tested by analyzing theaffinity and function of these interactions after exposure to thetherapeutic agent by standard pharmacokinetic measurements of affinity(Kd and Vmax etc) using synthetic peptides or recombinant proteinscorresponding to functional domains of the PS1 gene, the PS2 gene orother presenilin homologues. Another method for assaying the effect ofany interactions involving functional domains such as the hydrophilicloop is to monitor changes in the intracellular trafficking andpost-translational modification of the relevant genes by in situhybridization, immunohistochemistry, Western blotting and metabolicpulse-chase labelling studies in the presence of, and in the absence of,the therapeutic agents. A further method is to monitor the effects of"downstream" events including (i) changes in the intracellularmetabolism, trafficking and targeting of APP and its products; (ii)changes in second messenger events, e.g., cAMP intracellular Ca⁺⁺,protein kinase activities, etc.

Based on the locations of the familial AD mutations, the position ofdivergent primary sequence and the general topology of the PS1 and PS2proteins, it is proposed that at least three domains may providefunctional specificity to the presenilins. These functional domains are(1) the N-terminus (unique sequence in PS1 and PS2); (2) the TM6→7 loop(clustered mutations in the flanking conserved hydrophobic sequences andunique internal sequence); (3) the TM1, TM2 domains and TM1→2 linkingsequence (concentration of several familial AD mutations) and (4) theC-terminus. To isolate proteins that interact with these functionaldomains, screening for presenilin binding proteins is carried out usingGST-fusion constructs and synthetic peptides corresponding to theseregions. For example, for PS2, GST-fusion peptides are made includingsequences corresponding to amino acids 1 to 87 (N-terminus) or 272-390(TM6→7 loop) or a synthetic peptide is made corresponding to amino acids107 to 134 (TM1→2 link); for PS1, GST-fusion peptides are made includingsequences corresponding to amino acids 1 to 81 (N-terminus) or 266 to410 (TM6→7 loop) or a synthetic peptide is made corresponding to aminoacids 101 to 131 (TM1→2 link). The following methods may be employed toisolate presenilin binding proteins:

(1) direct extraction by affinity chromatography using GST-fusionproteins and synthetic peptides;

(2) co-isolation of presenilins and bound proteins byimmunoprecipitation;

(3) Biomolecular Interaction Assay (BIAcore) utilizing a GST-fusioncapture system; and

(4) Two-Hybrid yeast systems.

1. GST-Presenilin Fusion Protein & Synthetic Peptide AffinityChromatography.

GST-fusion proteins containing the N-terminus and TM6→7 loop sequencesfor PS1 and PS2 are used to probe human brain homogenates and theisolated collection of proteins is separated by SDS-PAGE andmicrosequenced (Phizicky and Fields, 1995). To ensure that the bandbeing sequenced contains only one protein species, the presenilin-fusionand binding proteins are separated by 2D gel electrophoresis prior totransfer and sequencing. For proteins with a blocked N-terminus, anadditional HPLC purification and cleavage (CNBr and/or trypsin) of theparticular binding protein is used to release peptide fragments. Furtherpurification by HPLC and microsequencing by conventional methodsprovides internal sequence data on such blocked proteins.

The TM1→2 linking sequence is predicted to reside on the opposite sideof the membrane to that of the N-terminal and TM6→7 loop and may beimportant in transmembrane communication. This is supported by theTyr115His mutation which was observed in a pedigree with early onsetfamilial AD (30-40 years) and by additional mutations in the TM1/2helices which might be expected to destabilise the loop. The TM1→2 loopis relatively short (PS1: residues 101-131; PS2: residues 107-134)making these sequence more amenable to convention peptide synthesis. ThePS1 fragment (31-mer) has been synthesised containing an additionalC-terminal cysteine residue. This peptide will be used to create anaffinity substrate for affinity chromatography (Sulfo-link; Pierce) toisolate binding proteins for microsequencing. A peptide corresponding tothe PS2 sequence is similarly synthesised and used to screen fordistinct binding proteins.

2. Co-Immunoprecipitation of PS1/PS2 and Bound Proteins

An additional technique for the isolation of the presenilins and theirassociated proteins is direct immunoprecipitation with antibodies. Thisprocedure has been successfully used, for example, to isolate many ofthe synaptic vesicle associated proteins (Phizicky & Fields, 1994).

3. Biomolecular Interaction Assay (BIAcore)

A useful method for the detection and isolation of binding proteins isthe BIAcore system developed by Pharmacia Biosensor and described in themanufacturer's protocol (LKB Pharmacia, Sweden). This system uses anaffinity purified anti-GST antibody to immobilize GST-fusion proteinsonto a sensor chip. The sensor utilizes surface plasmon resonance whichis an optical phenomenon that detects changes in refractive indices. Ahomogenate of a tissue of interest is passed over the immobilized fusionprotein and protein-protein interactions are registered as changes inthe refractive index. This system can be used to determine the kineticsof binding, to assess whether any observed binding is of physiologicalrelevance.

4. Two-Hybrid Yeast System

The Two-Hybrid system takes advantage of transcriptional factors thatare composed of two physically separable, functional domains (Phizickyand Fields, 1994, supra). The most commonly used is the yeast GAL4transcriptional activator consisting of a DNA binding domain and atranscriptional activation domain. Two different cloning vectors areused to generate separate fusions of the GAL4 domains to genes encodingpotential binding proteins. The fusion proteins are co-expressed,targeted to the nucleus and, if interactions occur, activation of areporter gene (e.g. lacZ) produces a detectable phenotype. For example,the Clontech Matchmaker System-2 may be used to screen the Clontechbrain cDNA GAL4 activation domain fusion library with presenilin GAL4binding domain fusion clones (Clontech, Palo Alto, Calif.).

Identification of Small Molecules with Presenilin Binding Capacity

Small molecule-based therapies are particularly preferred because suchmolecules are more readily absorbed after oral administration, havefewer potential antigenic determinants, and/or are more likely to crossthe blood brain barrier than larger, protein-based pharmaceuticals. Inlight of the present disclosure, one of ordinary skill in the art isenabled to develop drug screening methodologies which will be useful inthe identification of candidate small molecule pharmaceuticals for thetreatment of Alzheimer's Disease. In particular, one is enabled toscreen large libraries of small molecules in order to identify thosewhich bind to the normal and/or mutant PS1 or PS2 protein and which,therefore, are candidates for modifying the in vivo activity of thenormal or mutant presenilin proteins. Furthermore, one is enabled toidentify small molecules which selectively or preferentially bind to amutant form of a presenilin protein and which, therefore, may haveparticular utility in treating heterozygous victims of this dominantautosomal disease.

Methods for screening small molecule libraries for candidateprotein-binding molecules are well known in the art and, in light of thepresent disclosure, may now be employed to identify compounds which bindto the normal or mutant forms of a presenilin. Briefly, in oneembodiment, either a normal or mutant PS1 or PS2 protein may beimmobilized on a substrate such as a column or filter, and a solutionincluding the test compound(s) is contacted with the presenilin proteinunder conditions which are permissive for binding. The substrate is thenwashed with a solution which substantially reflects physiologicalconditions to remove unbound or weakly bound small molecules. A secondwash may then elute those compounds which strongly bound to theimmobilized normal or mutant presenilin. Alternatively, the smallmolecule test compounds may be immobilized and a solution of normal ormutant PS1 or PS2 may be contacted with the column, filter or othersubstrate. The ability of the presenilin to bind to the small moleculesmay be determined as above or a labelled form of presenilin (e.g.,radio-labelled or chemiluminescent) may be used to more rapidly assessbinding to the substrate-immobilized compound(s). In addition, as bothPS1 and PS2 are believed to be membrane associated proteins, it may bepreferred that the presenilin proteins be incorporated into lipidbilayers (e.g., liposomes) to promote their proper folding. Suchpresenilin-liposomes may be immobilized on substrates (either directlyor by means of another element in the liposome membrane), passed oversubstrates with immobilized small molecules, or used in any of a varietyof other well known binding assays for membrane proteins. In anotherseries of embodiments, either normal or mutant, free or membrane-boundPS1 or PS2 may be mixed in a solution with the candidate compound(s)under conditions which are permissive for binding, and the presenilinmay be immunoprecipitated. Small molecules which co-immunoprecipitatewith a presenilin may then be identified. As will be obvious to one ofordinary skill in the art, there are numerous other methods of screeningindividual small molecules or large libraries of small molecules (e.g.,phage display libraries) to identify compounds which bind to normal ormutant presenilins. All of these methods comprise the step of mixingnormal or mutant presenilin with test compounds, allowing for binding(if any), and assaying for bound complexes. All such methods are nowenabled by the present disclosure of purified the presenilin I andpresenilin II proteins.

Because the normal physiological roles of PS1 and PS2 are still unknown,compounds which bind to normal or mutant or both forms of thesepresenilins may have utility in treatments. Compounds which bind only toa normal presenilin may, for example, act as enhancers of its normalactivity and thereby at least partially compensate for the lost orabnormal activity of mutant forms of the presenilin in Alzheimer'sDisease victims. Compounds which bind to both normal and mutant forms ofa presenilin may have utility if they differentially affect theactivities of the two forms so as to alleviate the overall departurefrom normal function. Alternatively, blocking the activity of bothnormal and mutant forms of either PS1 or PS2 in heterozygotes may haveless severe physiological and clinical consequences than the normalprogress of the disease and, therefore, compounds which bind to andinhibit the activity of both normal and mutant forms of a presenilin mayhave utility. Preferably, however, compounds are identified which have ahigher affinity of binding to mutant presenilin than to normal presnilin(e.g., 5-10 fold higher K_(a)) and which selectively or preferentiallyinhibit the activity of the mutant form. Such compounds may beidentified by using any of the techniques described above and by thencomparing the binding affinities of the candidate compound(s) for thenormal and mutant forms of PS1 or PS2.

Once identified by the methods described above, the candidate compoundsmay then be produced in quantities sufficient for pharmaceuticaladministration or testing (e.g., μg or mg or greater quantities), andformulated in a pharmaceutically acceptable carrier (see, e.g.,Remington's Pharmaceutical Sciences, Gennaro, A., ed., Mack Pub., 1990,the disclosure of which is incorporated herein by reference). Thesecandidate compounds may then be administered to Alzheimer's patients oranimal models of Alzheimer's Disease. The animal models described andenabled herein are of particular utility in further testing candidatesmall molecules which bind to normal or mutant presnilin for theirtherapeutic efficacy.

Once identified by the methods described above, the candidate compoundsmay also serve as "lead compounds" in the design and development of newpharmaceuticals. For example, as in well known in the art, sequentialmodification of small molecules (e.g., amino acid residue replacementwith peptides; functional group replacement with peptide or non-peptidecompounds) is a standard approach in the pharmaceutical industry for thedevelopment of new pharmaceuticals. Such development generally proceedsfrom a "lead compound" which is shown to have at least some of theactivity (e.g., PS1 binding ability) of the desired pharmaceutical. Inparticular, when one or more compounds having at least some activity ofinterest (e.g., PS1 binding) are identified, structural comparison ofthe molecules can greatly inform the skilled practitioner by suggestingportions of the lead compounds which should be conserved and portionswhich may be varied in the design of new candidate compounds. Thus, thepresent invention also provides a means of identifying lead compoundswhich may be sequentially modified to produce new candidate compoundsfor use in the treatment of Alzheimer's Disease. These new compoundsthen may be tested both for presnilin-binding (e.g., in the bindingassays described above) and for therapeutic efficacy (e.g., in theanimal models described herein). This procedure may be iterated untilcompounds having the desired therapeutic activity and/or efficacy areidentified.

Assays for Identifying Drugs Which Affect Presenilin Expression

In another series of embodiments, the present invention provides asaysfor identifying small molecules or other compounds which are capable ofinducing or inhibiting the expression of PS1, PS2 or otherpresenilin-related genes and proteins. The assays may be performed invitro using non-transformed cells, immortalized cell lines, orrecombinant cell lines In addition, the assays may detect the presenceof increased or decreased expression of PS1 , PS2 or otherpresenilin-related genes or proteins on the basis of increased ordecreased mRNA expression (using, e.g., the nucleic acid probesdisclosed and enabled herein), increased or decreased levels of PS1, PS2or other presenilin-related protein products (using, e.g., theanti-presnilin antibodies disclosed and enabled herein), or increased ordecreased levels of expression of a reporter gene (e.g., β-galactosidaseor luciferase) operatively joined to a presenilin 5' regulatory regionin a recombinant construct.

Thus, for example, one may culture cells known to express a particularpresenilin and add to the culture medium one or more test compounds.After allowing a sufficient period of time (e.g., 6-72 hours) for thecompound to induce or inhibit the expression of the presenilin, anychange in levels of expression from an established baseline may bedetected using any of the techniques described above and well known inthe art. In particularly preferred embodiments, the cells are from animmortalized cell line such as a human glioblastoma cell line or ahybridoma×glioma cell line. Using the nucleic acid probes and /orantibodies disclosed and anbled herein, detection of changes in theexpression of a presenilin, and thus identification of the compound asan inducer or repressor of presenilin expression, requires only routineexperimentation.

In particularly preferred embodiments, a recombinant assay is employedin which a reporter gene such a β-galactosidase or luciferase isoperably joined to the 5' regulatory regions of a presenilin gene. Suchregulatory regions may be easily isolated and cloned by one of ordinaryskill in the art in light of the present disclosure of the codingregions of these genes. The reporter gene and regulatory regions arejoined in-frame (or in each of the three possible reading frames) sothat transcription and translation of the reporter gene may proceedunder the control of the presenilin regulatory elements. The recombinantconstruct may then be introduced into any appropriate cell type althoughmammalian cells are preferred, and human cells are most preferred. Thetransformed cells may be grown in culture and, after establishing thebaseline level of expression of the reporter gene, test compounds may beadded to the medium. The ease of detection of the expression of thereporter gene provides for a rapid, high through-put assay for theidentification of inducers and repressors of the presenilin gene.

Compounds identified by this method will have potential utility inmodifying the expression of the PS1, PS2 or other presenilin-relatedgenes in viva. These compounds may be further tested in the animalmodels disclosed and enabled herein to identify those compounds havingthe most potent in vivo effects. In addition, as described above withrespect to small molecules having presenilin-binding activity, thesemolecules may serve as "lead compounds" for the further development ofpharmaceuticals by, for example, subjecting the compounds to sequentialmodifications, molecular modeling, and other routine procedures employedin rational drug design.

Identification of a homologue of the ARMP (PS1) gene in C. elegans

A homologue of the presenilin genes has been found in C. elegans. Thishomologue is designated SEL-12.

Missense and nonsense mutations in this gene lead to an incompletelypenetrant defect in intracellular signal transduction pathways mediatedby the Notch/Lin-12 gene (Levitan, 1995). The Notch/Lin-12 gene mediatesinter-cellular signalling and cell fate determination during embryogenesis.

By determining the biology of this C. elegans gene, one obtains asimpler model on which one can study potential therapeutics formanipulation of the system.

By examining the relationship between Notch/Lin-12 genes and the humanpresenilins, Drosophila DmPS and C. elegans SEL-12, one may elucidatethe general biochemical functions of the presenilins and identifyupstream and downstream genes in the pathway which can be modifiedtherapeutically by drugs. Notch is involved in cell fate decisions inembryo genesis. These same cell fate decisions may be reactivated afterinjury due to genetic or environmental agents. If the presenilins,amyeloid precursor protein (APP), or apolipoprotein E (ApoE) areinvolved in Notch mediated responses to injury, or responses mediated byother genes, which lead to regeneration or degeneration decisionssimilar to those occurring in embryo genesis (differentiation versusdegeneration) then knowledge of this pathway can be exploited to developdrugs to suppress degenerative response and augment normal regenerativeresponse. The C. elegans and D. melanogaster models provide convenientways to (1) define the genes involved in Notch-presenilin interactions;(2) determine the structural nature of these interactions and effects ofmutations on these interactions; and (3) develop and test compoundsbased on the data from (1) and (2) to modulate these interactions. Thereis good evidence APP and ApoE are involved in injury repair mechanisms.

This observation suggests that the presenilin genes may have similarfunctions and that mutations in the presenilin genes may alter theeffectiveness of intracellular signalling pathways. Modification of asignalling pathway in the presence of presenilin mutations could be usedas a means to define treatments for Alzheimer's Disease (AD). Thepotential mechanisms by which mutations in the presenilin genes mightalter intracellular signalling pathways include the following:

First, the presenilin gene could act as a co-receptor with otherreceptors such as Notch/Lin-12.

Second, the presenilins could be involved as downstream effectors in thesignal pathway (for instance, perhaps acting as a second messenger oramplification system through modification of calcium metabolism, etc.).Alternatively, the presenilin proteins may be involved in theintracellular processing of membrane proteins such as Notch/Lin-12 orthe βAPP proteins. This role in protein processing would be in keepingwith the intracellular localization of the presenilin proteins in theendoplasmic reticulum and Golgi apparatus. The alteration of proteinprocessing could occur shortly after synthesis of the native membraneproteins (e.g. the presenilins may have a role in chaperone, proteinfolding, and membrane insertion events). Alternatively, the presenilinsmight have a function in the processing of other enzymes andintracellular proteins which are necessary for the modification of cellsurface proteins such as Notch/Lin-12 and βAPP (e.g. the presenilins maybe involved in the processing of α, β and ∝ secretase which are involvedin βAPP metabolism). The presenilins could also be involved in theintracellular transport of fragments of cell membrane proteins (e.g. theC-terminal stump of Notch/Lin-12 or βAPP), as for instance in thetranslocation of Notch/Lin-12 fragments into the nucleus where theyaffect transcription.

Disturbances of function caused by mutations in the presenilin genescould be modified or corrected by drug treatment. These drugs could bescreened for by using one or more of the following assays:

PC12 cells (ATCC, Rockville, Md.) are stably transfected by standardlipofectamine or calcium phosphate methods with wild-type and mutantpresenilin cDNA's cloned into the vector pcDNA3 (Invitrogen, San Diego,Calif.) and induced to differentiate into neuron-like cell types by theadministration of nerve growth factor (Gibco/BRL, MD) (Obermeier et al.,(1994), these cells return to the undifferentiated state afterwithdrawal of the nerve growth factor. Differences in the rates anddegrees of differentiation between PC12 cells transfected with wild-typeor mutant presenilin cDNA's can be quantitated and an assay is therebyobtained, in which reversion to the wild-type phenotype is scored afterthe administration of a variety of chemical compounds available from apharmaceutical/chemical combinatorial library.

A similar assay can be derived based upon Notch signalling pathways inother cell types including Drosophila melanogaster cells (PC or S2cells) transfected with activated (mutant) Notch cDNA clones, ormammalian P19 cells also transfected with activated Notch cDNA clones.

By double-transfecting the Drosophila or P19 cells with the activatedNotch clone, and with either wild-type or mutant presenilin cDNA's, itis possible to discern a difference in the rate of differentiation incell types transfected with wild-type presenilin compared to cell typesco-transfected with the mutant presenilin cDNA. Again, by challengingthese cell types and scoring the phenotype of suppression ofdifferentiation into neuronal cells in the presence of chemicals drawnfrom a chemical combinatorial library, compounds may be identified whichreverse the effect of mutant presenilin genes on this Notch-mediatedphenotype.

A similar effect can also be achieved in C. elegans and Drosophilamelanogaster whole animals. In this system, animals bearing eitherwild-type Notch/Lin-12 genes or activated mutations in the Notch/Lin-12gene also carry either wild-type or mutant human presenilin transgenes.

C. elegans and D. melanogaster are transformed by microinjectionoocytes.

The presenilin transgenes are cloned downstream of the C. elegansheat-shock promoter element in an expression vector such as pPD69.78 hsp16.2 or pPD69.3 hsp 16-41, which are public domain vectors for creatingC. elegans transgenic lines in which the gene of interest is under thecontrol of an inducible heat shock promoter element.

Identification of a homologue of the PS1 (ARMP) gene in D. melanogaster

A homologue of the presenilin genes has been found in D. melanogaster.This homologue is designated the DmPS gene.

Redundant oligonucleotides coding for highly conserved regions of thepresenilin/sel 12 portions were prepared and used to identify relevantmRNAs from adult and embryonic D. melanogaster. These mRNAs weresequenced and shown to contain an open reading frame with a putativeamino acid sequence highly homologous to that of the human presenilins.The DmPS cDNA is identified as SEQ ID NO:165.

This sequence encodes a polypeptide of 541 amino acids (SEQ ID NO:166)with about 52% identity to the human presenilins.

The DNA sequence of the DmPS gene as cloned has been incorporated into aplasmid Bluescript. This stable vector was been deposited at ATCC,Rockville, Md., under ATCC accession number 97428 on Jan. 26, 1996.

The structure of the D. melanogaster homologue is similar to that of thehuman presenilins with at least seven putative transmembrane domains(Kyte-Doolittle hydrophobicity analyses using window of 15 and cut-offof 1.5). Evidence of at least one alternative splice form was detectedin that clone pds13 contained an ORF of 541 amino acids, while clonespds7, pds14 and pds1 lacked nucleotides 1300-1341 inclusive. Thisalternative splicing would result in the alteration of Gly to Ala atresidue 384 in the putative TM6-TM7 loop, and in-frame fusion to the Gluresidue at codon 399 of the longer ORF. The principal differencesbetween the amino acid sequence of the D. melanogaster and human geneswere in the N-terminal acid hydrophilic domain and in the acidhydrophilic portion of the TM6-TM7 loop. The residues surrounding theTM6→TM7 loop are especially conserved (residues 220-313 and 451-524)suggesting that these are functionally important domains. Sixteen out oftwenty residues mutated in human PS1 or PS2 and giving rise to human FADare conserved in the D. melanogaster homologue.

The D. melanogaster presenilin (DmPS) gene can be targeted for nullmutations (either spontaneous deletions/rearrangements or mutationsinserted by standard P-element mutagenesis techniques). Wild-type ormutant transgenes can be over-expressed using standard transgenicmethods in which a cDNA minigene under the control of one or morepromoter element such as the GAL4-UAS system is microinjected intooocytes (Brand and Perrimon, 1993). The presence or absence of aphenotype can be scored by anatomic and pathologic inspection, forexample for defects in Notch mediated developmental pathways(Campos-Ortega, 1991) similar to those seen in C. elegans with defectsin the sel-12 gene, which is the C. elegans homologue of the humanpresenilin genes (Levitan & Greenwald, 1995), or for behaviouraldefects, for example defects in memory and learning, using methods usedto characterize this in D. melanogaster mutants such as "dunce" and"ruderbaker" (Davis, 1996), or by biochemical methods (e.g. detection ofdefects in the handling of APL-1 which is the D. melanogaster homologueof the human APP genes thought to be involved in AD). Drosophila modelscan be used to explore the general biochemical function of the DmPS geneby analyzing the effect of null (knockout) mutations, the effects, inthe D. melanogaster, of missense mutations gene similar to thoseobserved in the human presenilin genes in human early onset AD and theeffects of over-expressing wild-type or mutant DmPS. Such models canalso be used to determine whether the human presenilin genes cancomplement loss of function mutations in the Drosophila DmPS gene,providing guidance for gene replacement therapy in humans with mutantpresenilin genes). These models can also be used to test the efficacy ofdrugs intended to affect the biochemical processes which cause AD. Suchdrug screening is carried out by observing which drugs correct orimprove a phenotype associated with a DmPS gene mutation.

The DmPS gene can also be used to define other proteins which interactwith the Drosophila DmPS homologue. The human equivalents of anyinteracting proteins identified in D. melanogaster can be isolated usinga variety of methods including PCR with redundant oligonucleotides, andprotein database searches. The function of the interacting protein canalso be more conveniently examined in D. melanogaster by genetic andbiochemical means. Methods for identifying and characterizing suchinteracting proteins include yeast-2-hybrid, affinity chromatographyusing the D. melanogaster protein as the affinity reagent), andimmunoprecipitation (with or without cross-linking) methods (Phizicky &Fields, 1995). The kinetics, biochemistry, and structural basis of thisinteraction can be verified using BlAcore analysis or crystallographyetc and would serve as a basis for the development of compounds toaugment defective interactions or impede pathological interactions dueto mutations in the D. melanogaster presenilin. The function of theinteracting protein can also be more easily worked out by genetic andbiochemical means in D. melanogaster than in a higher animal model.

Additionally, the DmPS gene can be used in genetic paradigms to identifyother genes which interact with the presenilins and which can modulatethe effect of the mutant isoforms of the presenilins. Cross breedingexperiments with other mutant D. melanogaster lines provide a means ofmapping and cloning other genes which suppress or enhance the phenotypeassociated with mutations in the D. melanogaster presenilin. Subsequentisolation of the human homologues of such modifier genes will identifygene products capable of modulating the effect of mutations in the humanpresenilin genes. The biochemical effect of these modulating geneproducts can be modelled and used to develop pharmaceuticals to treatAD. Part of or all of the modulating gene product itself can beadministered as a treatment for AD by a variety of means includingprotein infusion and gene therapy.

Screening and Diagnosis for Alzheimer's Disease

General Diagnostic Methods

The presenilin and presenilin-related genes and gene products, as wellas other products derived therefrom (e.g., probes, antibodies), will beuseful in the diagnosis of Alzheimer's Disease, presenile and seniledementias, psychiatric diseases such as schizophrenia, depression, etc.,and neurologic diseases such as stroke and cerebral hemorrhage--all ofwhich are seen to a greater or lesser extent in symptomatic subjectsbearing mutations in the PS1 or PS2 genes or in the APP gene. Diagnosisof inherited cases of these diseases can be accomplished by methodsbased upon the nucleic acids (including genomic and mRNA/cDNAsequences), proteins, and/or antibodies disclosed and enabled herein.Preferably, the methods and products are based upon the human PS1 or PS2nucleic acids, proteins or antibodies disclosed herein. As will beobvious to one of ordinary skill in the art, however, the significantevolutionary conservation of large portions of the PS1 and PS2nucleotide and amino acid sequences, even in species as diverse ashumans and C. elegans and Drosophila, allow the skilled artisan to makeuse of such non-human presenilin-homologue nucleic acids, proteins andantibodies even for applications directed toward human or othermammalian subjects. Thus, for brevity of exposition, but withoutlimiting the scope of the invention, the following description willfocus upon uses of the human homologues of PS1 and PS2. It will beunderstood, however, that homologous sequences from other species,including those disclosed herein, will be equivalent for many purposes.

As will be appreciated by one of ordinary skill in the art, the choiceof diagnostic methods of the present invention will be influenced by thenature of the available biological samples to be tested and the natureof the information required. PS1, for example, is highly expressed inbrain tissue but brain biopsies are invasive and expensive procedures,particularly for routine screening. Other tissues which express PS1 atsignificant levels, however, may demonstrate alternative splicing (e.g.,white blood cells) and, therefore, PS1 mRNA or protein from such cellsmay be less informative. Thus, assays based upon a subject's genomic DNAmay be the preferred methods for PS1 diagnostics as no information willbe lost due to alternative splicing and because essentially any nucleatecells may provide a usable sample. Diagnostics based upon otherpresenilin-related proteins are subject to similar considerations:availability of tissues, levels of expression in various tissues, andalternative translation products resulting from alternative mRNAsplicing.

When a diagnostic assay is to be based upon presenilin-related proteins,a variety of approaches are possible. For example, diagnosis can beachieved by monitoring differences in the electrophoretic mobility ofnormal and mutant proteins. Such an approach will be particularly usefulin identifying mutants in which charge substitutions are present, or inwhich insertions, deletions or substitutions have resulted in asignificant change in the molecular mass of the resultant protein.Alternatively, diagnosis may be based upon differences in theproteolytic cleavage patterns of normal and mutant proteins, differencesin molar ratios of the various amino acid residues, or by functionalassays demonstrating altered function of the gene products. In somepreferred embodiments, protein-based diagnostics will employ differencesin the ability of antibodies to bind to normal and mutantpresenilin-related proteins (especially PS1 or PS2). Such diagnostictests may employ antibodies which bind to the normal proteins but not tomutant proteins, or vice versa. Because a limited number of mutationshave been identified in the PS1 and PS2 genes/proteins, and becausethese mutations appear to be themselves conserved, it is currentlypreferred that antibodies capable of selectively binding to mutantproteins be employed. In particular, an assay in which a plurality ofmonoclonal antibodies, each capable of binding to a mutant epitope, maybe employed. The levels of anti-mutant antibody binding in a sampleobtained from a test subject (visualized by, for example,radiolabelling, ELISA or chemiluminescence) may be compared to thelevels of binding to a control sample. Such antibody diagnostics may beused for in situ immunohistochemistry using biopsy samples of CNStissues obtained antemortem or postmortem, including neuropathologicalstructures associated with these diseases such as neurofibrillarytangles and amyloid plaques, or may be used with fluid samples such acerebrospinal fluid or with peripheral tissues such as white bloodcells.

When the diagnostic assay is to be based upon nucleic acids from asample, either mRNA or genomic DNA may be used. When mRNA is used from asample, many of the same considerations apply with respect to sourcetissues and the possibility of alternative splicing. That is, there maybe little or no expression of transcripts unless appropriate tissuesources are chosen or available, and alternative splicing may result inthe loss of some information. With either mRNA or DNA, standard methodswell known in the art may be used to detect the presence of a particularsequence either in situ or in vitro (see, e.g. Sambrook et al., eds.(1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press,Cold Spring Harbor, N.Y.).

For in situ detection of a mutant PS1, PS2 or other presenilin-relatednucleic acid sequence, a sample of tissue may be prepared by standardtechniques and then contacted with a probe, preferably one which islabelled to facilitate detection, and an assay for nucleic acidhybridization is conducted under stringent conditions which permithybridization only between the probe and highly or perfectlycomplementary sequences. Because most of the PS1 and PS2 mutationsdetected to date consist of a single nucleotide substitution, highstringency hybridization conditions will be required to distinguishnormal sequences from most mutant sequences. As an example only, thefollowing procedure may be employed on a subject: A rat animal model isanesthetized and transcardially perfused with cold PBS, followed byperfusion with a formaldehyde solution. The brain or other tissue ofinterest is then removed, frozen in liquid nitrogen, and cut into thinmicron sections. The sections are placed on slides and incubated inproteinase K. Following rinsing in DEP, water and ethanol, the slidesare placed in prehybridization buffer. A radioactive probe correspondingto the selected oligonucleotide is incubated with the sectioned braintissue. After incubation and air drying, the labeled areas arevisualized by autoradiography. Dark spots on the tissue sample indicatehybridization of the probe with brain mRNA, demonstrating expression ofthe nucleic acid sequence.

A significant advantage of the use of either DNA or mRNA is the abilityto amplify the amount of genetic material using the polymerase chainreaction (PCR), either alone (with genomic DNA) or in combination withreverse transcription (with mRNA to produce cDNA). Because it iscontemplated that such PCR-based genetic methods may be preferredcommercial embodiments for diagnostic screenings, a detailed descriptionof several embodiments is presented below.

Screening for Alzheimer's Disease Linked to Chromosome 14

Screening for Alzheimer's Disease as linked to chromosome 14 may now bereadily carried out because of the knowledge of the mutations in thegene.

Individuals with a high risk for Alzheimer's Disease (present in familypedigree) or, individuals not previously known to be at risk, or peoplein general may be screened routinely using probes to detect the presenceof a mutant PS1 gene by a variety of techniques. Genomic DNA used forthe diagnosis may be obtained from body cells, such as those present inthe blood, tissue biopsy, surgical specimen, or autopsy material. TheDNA may be isolated and used directly for detection of a specificsequence or may be PCR amplified prior to analysis. RNA or cDNA may alsobe used. To detect a specific nucleic acid sequence, hybridization usingspecific oligonucleotides, direct nucleotide sequencing, restrictionenzyme digest, RNase protection, chemical cleavage, or ligase-mediateddetection may be used. Oligonucleotides specific to mutant sequences canbe chemically synthesized and labelled radioactively with isotopes, ornon-radioactively using biotin tags, and hybridized to individualsamples immobilized on membranes or other solid-supports by dot-blot ortransfer from gels after electrophoresis. The presence or absence ofthese mutant sequences is then visualized using methods such asautoradiography, fluorometry, or calorimetric reaction. Examples ofsuitable PCR primers which are useful for example in amplifying portionsof the subject sequence containing the aforementioned mutations are setout in Table 5. This table also sets out changes in restriction enzymesites to provide a useful diagnostic tool as defined herein. Direct DNAsequencing reveals sequence differences between normal and mutant PS1DNA. Cloned genomic or cDNA segments may be used as probes to detectspecific DNA segments. PCR can be used to enhance the sensitivity ofthis method. PCR is an enzymatic amplification directed bysequence-specific primers, and involves repeated cycles of heatdenaturation of the DNA, annealing of the complementary primers andextension of the annealed primer with a DNA polymerase. This results inan exponential increase of the target DNA.

Other nucleotide sequence amplification techniques may be used, such asligation-mediated PCR, anchored PCR and enzymatic amplification as willbe understood by those skilled in the art.

Sequence alterations may also generate fortuitous restriction enzymerecognition sites which are revealed by the use of appropriate enzymedigestion followed by gel-blot hybridization. DNA fragments carrying thesite (normal or mutant) are detected by their increase or reduction insize, or by the increase or decrease of corresponding restrictionfragment numbers. Genomic DNA samples may also be amplified by PCR priorto treatment with the appropriate restriction enzyme and the fragmentsof different sizes are visualized, for example under UV light in thepresence of ethidium bromide, after gel electrophoresis.

Genetic testing based on DNA sequence differences may be achieved bydetection of alteration in electrophoretic mobility of DNA fragments ingels. Small sequence deletions and insertions can be visualized by highresolution gel electrophoresis of single stranded DNA, or as changes inthe migration pattern of DNA heteroduplexes in non-denaturing gelelectrophoresis. Alternatively, a single base substitution mutation maybe detected based on differential PCR product length in PCR. The PCRproducts of the normal and mutant gene may be differentially detected inacrylamide gels.

Nuclease protection assays (S1 or ligase-mediated) also reveal sequencechanges at specific locations.

Alternatively, to confirm or detect a polymorphism resulting inrestriction mapping changes, ligated PCR, ASO, REF-SSCP chemicalcleavage, endonuclease cleavage at mismatch sites or SSCP may be used.Both REF-SSCP and SSCP are mobility shift assays which are based uponthe change in conformation due to mutations.

DNA fragments may also be visualized by methods in which the individualDNA samples are not immobilized on membranes. The probe and targetsequences may be in solution or the probe sequence may be immobilized.Autoradiography, radioactive decay, spectrophotometry and fluorometrymay also be used to identify specific individual genotypes. Mutationscan also be detected by direct nucleotide sequencing.

According to an embodiment of the invention, the portion of the cDNA orgenomic DNA segment that is informative for a mutation can be amplifiedusing PCR. For example, the DNA segment immediately surrounding the C410 Y mutation acquired from peripheral blood samples from an individualcan be screened using the oligonucleotide primers TGGAGACTGGAACACAAC(SEQ ID NO:127) and GTGTGGCCAGGGTAGAGAACT (SEQ ID NO:128). This regionwould then be amplified by PCR, the products separated byelectrophoresis, and transferred to membrane. Normal and mutant PCRproducts may then be detected using, for example, hybridization oflabeled oligonucleotide probes and autoradiography, RFLP analysis, ordirect sequencing.

Screening for Alzheimer's Disease linked to Chromosome 1

Screening for Alzheimer's Disease linked to mutations of the PS2 genemay now be conveniently carried out.

General screening methods are described above in relation to thedescribed mutations in the PS1 gene. These described methods can bereadily applied and adapted to detection of the described chromosome 1mutations, as will be readily understood by those skilled in the art.

In accordance with one embodiment of the invention, the Asn141Ilemutation is screened for by PCR amplification of the surrounding DNAfragment using the primers:

5'-CATTCACTGAGGACACACC (end-labelled) and (SEQ ID NO:175)

5'-TGTAGAGCACCACCAAGA (unlabelled) (SEQ ID NO:176)

Any tissue with nucleated cells may be examined. The amplified productsmay be separated by, for example, electrophoresis and an autoradiogramor other standard method may be employed to detect mutant sequences.

In accordance with a further embodiment, the Met239Val mutation isscreened for by PCR amplification of its surrounding DNA fragment usingthe primers:

5'-GCATGGTGTGCATCCACT and (SEQ ID NO:177)

5'-GGACCACTCTGGGAGGTA (SEQ ID NO:178)

The amplified products are separated and an autoradiogram or otherstandard method may be employed to detect mutant sequences.

In accordance with a further embodiment, the Ile420Thr mutation isscreened for by PCR amplification of genomic DNA using primers 5' TGCTGC TTG CTG TGT TCA 3' (SEQ ID NO:161) and 5' CCA TGT CCC TCA GAT GTA GA3' (SEQ ID NO:162) to generate a 146 base pair product which can beprobed with allele specific oligonucleotides for the wild-type (5' CATCTC CAT CAC GTT CG 3'; SEQ ID NO:163) and mutant (5' CAT CTC CAC CAC GTTCG 3'; SEQ ID NO:164) sequences.

The same primer sets may be used to detect the mutations by means ofother methods such as SSCP, chemical cleavage, DGGE, nucleotidesequencing, ligation chain reaction and allele specificoligonucleotides. As will be understood by those skilled in the art,other suitable primer pairs may be devised and used.

In inherited cases, as the primary event, and in non-inherited cases asa secondary event due to the disease state, abnormal processing of PS1,PS2, APP or proteins reacting with PS1, PS2, or APP may occur. This canbe detected as abnormal phosphorylation, glycosylation, glycationamidation or proteolytic cleavage products in body tissues or fluids,e.g., CSF or blood.

Diagnosis of non-inherited cases also can be made by observation ofalterations in the presenilin transcription, translation, andpost-translational modification and processing as well as alterations inthe intracellular and extracellular trafficking of presenilin geneproducts in the brain and peripheral cells. Such changes will includealterations in the amount of presenilin messenger RNA and/or protein,alteration in phosphorylation state, abnormal intracellularlocation/distribution, abnormal extracellular distribution, etc. Suchassays will include: Northern Blots (with presenilin-specific andnon-specific nucleotide probes which also cross-react with other membersof the gene family), and Western blots and enzyme-linked immunosorbentassays (ELISA) (with antibodies raised specifically to: a presenilin; tovarious functional domains of a presenilin; to other members of thehomologous gene family; and to various post-translational modificationstates including glycosylated and phosphorylated isoforms). These assayscan be performed on peripheral tissues (e.g. blood cells, plasma,cultured or other fibroblast tissues, etc.) as well as on biopsies ofCNS tissues obtained antemortem or postmortem, and upon cerebrospinalfluid. Such assays might also include in-situ hybridization andimmunohistochemistry (to localized messenger RNA and protein to specificsubcellular compartments and/or within neuropathological structuresassociated with these diseases such as neurofibrillary tangles andamyloid plaques).

In accordance with the present invention, diagnostic kits are alsoprovided which will include the reagents necessary for theabove-described diagnostic screens. For example, kits may be providedwhich include antibodies or sets of antibodies which are specific to oneor more mutant epitopes. These antibodies may, in particular, belabelled by any of the standard means which facilitate visualization ofbinding. Alternatively, kits may be provided in which oligonucleotideprobes or PCR primers are present for the detection and/or amplificationof mutant PS1, PS2 or other presenilin-related nucleotide sequences.Again, such probes may be labelled for easier detection of specifichybridization. As appropriate to the various diagnostic embodimentsdescribed above, the oligonucleotide probes or antibodies in such kitsmay be immobilized to substrates and appropriate controls may beprovided.

Therapies

An important aspect of the biochemical studies using the geneticinformation of this invention is the development of therapies tocircumvent or overcome the PS1 or PS2 gene defect, and thus prevent,treat, control serious symptoms or cure the disease. In view ofexpression of the PS1 gene in a variety of tissues, one has to recognizethat Alzheimer's Disease may not be restricted to the brain, oralternatively that diseases manifest in other tissues may arise frommutations, mis-expression, mis-metabolism or other inherited or acquiredalteration in these genes and gene products.

Alzheimer's Disease manifests itself as a neurological disorder which inone of its forms is caused by a mutation in the PS1 gene and in anotherof its forms by a mutation in the PS2 gene, but such manifestation maybe caused by the mutations affecting other organ tissues, such as theliver, releasing factors which affect brain activity and ultimatelycause Alzheimer's Disease. Hence, in considering various therapies, itis understood that such therapies may be targeted at tissue other thanthe brain, such as heart, placenta, lung, liver, skeletal muscle, kidneyand pancreas, where PS1 or PS2 is also expressed.

The effect of these mutations in PS1 and PS2 apprently is a gain of anovel function or an acceleration of a normal function which causesaberrant processing of (APP) Amyloid Precursor Protein into Aβ peptide,abnormal phosphorylation homeostasis, and abnormal apoptosis in brain.These effects are direct or indirect and are consistent with dominantinheritance with adult onset of symptoms.

Therapy to reverse this will be by means of small molecules (drugs),recombinant proteins, antibodies or recombinant genes, to block theaberrant function by altering the structure of the mutant protein, byenhancing its metabolic clearance or inhibiting binding of ligands tothe mutant protein, or by inhibiting the channel function of the mutantprotein. The same effect might be gained by inserting a second mutantprotein by gene therapy similar to the correction of the "Deg 1(d)" and"Mec 4(d)" mutations in C. elegans by insertion of mutant transgenes.Alternately, overexpression of wild type PS1 protein or wild type PS2 orboth may correct the defect. This could be achieved by theadministration of drugs or proteins to induce the transcription andtranslation or inhibit the catabolism of the native PS1 and PS2proteins. It could also be accomplished by infusion of recombinantproteins or by gene therapy with vectors causing expression of thenormal protein at a high level or by modification of interactingproteins by the procedures described elsewhere herein.

Rationale for Therapeutic, Diagnostic, and Investigational Applicationsof the PS1 Gene and Gene Products as They Relate to the AmyloidPrecursor Protein

The Aβ peptide derivatives of APP are neurotoxic (Selkoe et al, 1994).APP is metabolized by passages through the Golgi network and then tosecretory pathways via clathrin-coated vesicles with subsequent passageto the plasma membrane where the mature APP is cleaved by α-secretase toa soluble fraction (Protease Nexin II) plus a non-amyloidogenicC-terminal peptide (Selkoe et al. 1995, Gandy et al. 1993).Alternatively, mature APP can be directed to the endosome-lysosomepathway where it undergoes β and α secretase cleavage to produce the Aβpeptides. The phosphorylation state of the cell determines the relativebalance of α-secretase (non-amyloidogenic) or Aβ pathways (amyloidogenicpathway) (Gandy et al. 1993). The phosphorylation state of the cell canbe modified pharmacologically by phorbol esters, muscarinic agonists andother agents, and appears to be mediated by cytosolic factors(especially protein kinase C) acting upon an integral membrane proteinin the Golgi network, which we propose to be the PS1, and members of thehomologous family (all of which carry several phosphorylation consensussequences for protein kinase C). Mutations in the PS1 gene will causealterations in the structure and function of the PS1 gene productleading to defective interactions with regulatory elements (eg. proteinkinase C) or with APP, thereby promoting APP to be directed to theamyloidogenic endosome-lysosome pathway. Environmental factors (viruses,toxins, and aging etc) may also have similar effects on PS1. To treatAlzheimer's Disease, the phosphorylation state of PS1 can be altered bychemical and biochemical agents (eg. drugs, peptides and othercompounds) which alter the activity of protein kinase C and otherprotein kinases, or which alter the activity of protein phosphatases, orwhich modify the availability of PS1 to be post-translationallymodified. The interactions between kinases and phosphatases with the PS1gene products (and the products of its homologues), and the interactionsof the PS1 gene products with other proteins involved in the traffickingof APP within the Golgi network can be modulated to decrease traffickingof Golgi vesicles to the endosome-lysosome pathway thereby promoting Aβpeptide production. Such compounds will include: peptide analogues ofAPP, PS1, and homologues of PS1 as well as other interacting proteins,lipids, sugars, and agents which promote differential glycosylation ofPS1 and its homologues; agents which alter the biologic half-life ofmessenger RNA or protein of PS1 and homologues including antibodies andantisense oligonucleotides; and agents which act upon PS1 transcription.

The effect of these agents in cell lines and whole animals can bemonitored by monitoring: transcription; translation; post-translationalmodification of PS1 (eg phosphorylation or glycosylation); andintracellular trafficking of PS1 and its homologues through variousintracellular and extracellular compartments. Methods for these studiesinclude Western and Northern blots; immunoprecipitation after metaboliclabelling (pulse-chase) with radio-labelled methionine and ATP, andimmunohistochemistry. The effect of these agents can also be monitoredusing studies which examine the relative binding affinities and relativeamounts of PS1 gene products involved in interactions with proteinkinase C and/or APP using either standard binding affinity assays orco-precipitation and Western blots using antibodies to protein kinase C,APP or PS1 and its homologues. The effect of these agents can also bemonitored by assessing the production of Aβ peptides by ELISA before andafter exposure to the putative therapeutic agent (Huang et al. 1993).The effect can also be monitored by assessing the viability of celllines after exposure to aluminum salts and to Aβ peptides which arethought to be neurotoxic in Alzheimer's Disease. Finally, the effect ofthese agents can be monitored by assessing the cognitive function ofanimals bearing: their normal genotype at APP or PS1 homologues; orbearing human APP transgenes (with or without mutations); or bearinghuman PS1 transgenes (with or without mutations); or a combination ofall of these.

Rationale for Therapeutic, Diagnostic, and Investigational Applicationsof the PS1 and PS2 Genes and Products

The PS1 gene product and the PS2 gene product have amino acid sequencehomology to human ion channel proteins and receptors. For instance, thePS2 protein shows substantial homology to the human sodium channelα-subunit (E=0.18, P=0.16, identities=22-27% over two regions of atleast 35 amino acid residues) using the BLASTP paradigm of Altschul etal. 1990. Other diseases (such as malignant hyperthermia andhyperkalemic periodic paralysis in humans and the neurodegenerative ofmechanosensory neurons in C. elegans) arise through mutations in ionchannels or receptor proteins. Mutation of the PS1 gene or the PS2 genecould affect similar functions and lead to Alzheimer's Disease and otherpsychiatric and neurological diseases. Based upon this, a test forAlzheimer's Disease can be produced to detect an abnormal receptor or anabnormal ion channel function related to abnormalities that are acquiredor inherited in the PS1 gene and its product, or in one of thehomologous genes such as PS2 and their products. This test can beaccomplished either in vivo or in vitro by measurements of ion channelfluxes and/or transmembrane voltage or current fluxes using patch clamp,voltage clamp and fluorescent dyes sensitive to intracellular calcium ortransmembrane voltage. Defective ion channel or receptor function canalso be assayed by measurements of activation of second messengers suchas cyclic AMP, cGMP tyrosine kinases, phosphates, increases inintracellular Ca²⁺ levels, etc. Recombinantly made proteins may also bereconstructed in artificial membrane systems to study ion channelconductance. Therapies which affect Alzheimer's Disease (due toacquired/inherited defects in the PS1 gene or PS2 gene; due to defectsin other pathways leading to this disease such as mutations in APP; anddue to environmental agents) can be tested by analysis of their abilityto modify an abnormal ion channel or receptor function induced bymutation in the PS1 gene or in one of its homologues. Therapies couldalso be tested by their ability to modify the normal function of an ionchannel or receptor capacity of the PS1 gene products and itshomologues. Such assays can be performed on cultured cells expressingendogenous normal or mutant PS1 genes/gene products or PS2 genes/geneproducts. Such studies can be performed in addition on cells transfectedwith vectors capable of expressing PS1, parts of the PS1 gene and geneproduct, mutant PS1, PS2 gene, parts of the PS2 gene and gene product,mutant PS2 gene or another homologue in normal or mutant form. Therapiesfor Alzheimer's Disease can be devised to modify an abnormal ion channelor receptor function of the PS1 gene or PS2 gene. Such therapies can beconventional drugs, peptides, sugars, or lipids, as well as antibodiesor other ligands which affect the properties of the PS1 or PS2 geneproduct. Such therapies can also be performed by direct replacement ofthe PS1 gene and/or PS2 gene by gene therapy. In the case of an ionchannel, the gene therapy could be performed using either mini-genes(cDNA plus a promoter) or genomic constructs bearing genomic DNAsequences for parts or all of the PS1 gene. Mutant PS1 or homologousgene sequences might also be used to counter the effect of the inheritedor acquired abnormalities of the PS1 gene as has recently been done forreplacement of the mec 4 and deg 1 in C. elegans (Huang and Chalfie,1994). The therapy might also be directed at augmenting the receptor orion channel function of the homologous genes such as the PS2 gene, inorder that it may potentially take over the functions of the PS1 generendered defective by acquired or inherited defects. Therapy usingantisense oligonucleotides to block the expression of the mutant PS1gene or the mutant PS2 gene, coordinated with gene replacement withnormal PS1 or PS2 gene can also be applied using standard techniques ofeither gene therapy or protein replacement therapy.

Protein Therapy

Treatment of Alzheimer's Disease can be performed by replacing themutant protein with normal protein, or by modulating the function of themutant protein. Once the biological pathway of the PS1 protein and thePS2 protein has been completely understood, it may also be possible tomodify the pathophysiologic pathway or pathways (eg. a signaltransduction pathway) in which these proteins participate, in order tocorrect the physiological defect.

To replace the mutant protein with normal protein, or with a proteinbearing a deliberate counterbalancing mutation it is necessary to obtainlarge amounts of pure PS1 protein or PS2 protein from cultured cellsystems which can express the protein. Delivery of the protein to theaffected brain areas or other tissues can then be accomplished usingappropriate packaging or administrating systems.

Gene Therapy

Gene therapy is another potential therapeutic approach in which normalcopies of the PS1 gene or the PS2 gene are introduced into patients tocode successfully for normal protein in several different affected celltypes. The gene must be delivered to those cells in a form in which itcan be taken up and code for sufficient protein to provide effectivefunction. Alternatively, in some neurologic mutants it has been possibleto prevent disease by introducing another copy of the homologous genebearing a second mutation in that gene or to alter the mutation, or useanother gene to block its effect.

Retroviral vectors can be used for somatic cell gene therapy especiallybecause of their high efficiency of infection and stable integration andexpression. The targeted cells however must be able to divide and theexpression of the levels of normal protein should be high because thedisease is a dominant one. The full length PS1 gene can be cloned into aretroviral vector and driven from its endogenous promoter or from theretroviral long terminal repeat or from a promoter specific for thetarget cell type of interest (such as neurons).

Other viral vectors which can be used include adeno-associated virus,vaccinia virus, bovine papilloma virus, or a herpesvirus such asEpstein-Barr virus.

Gene transfer could also be achieved using non-viral means requiringinfection in vitro. This would include calcium phosphate, DEAE dextran,electroporation, and protoplast fusion. Liposomes may also bepotentially beneficial for delivery of DNA into a cell. Although thesemethods are available, many of these are lower efficiency.

Antisense based strategies can be employed to explore PS1 gene functionand as a basis for therapeutic drug design. The principle is based onthe hypothesis that sequence-specific suppression of gene expression canbe achieved by intracellular hybridization between mRNA and acomplementary antisense species. The formation of a hybrid RNA duplexmay then interfere with the processing/transport/translation and/orstability of the target PS1 mRNA. Hybridization is required for theantisense effect to occur, however the efficiency of intracellularhybridization is low and therefore the consequences of such an event maynot be very successful. Antisense strategies may use a variety ofapproaches including the use of antisense oligonucleotides, injection ofantisense RNA and transfection of antisense RNA expression vectors.Antisense effects can be induced by control (sense) sequences, however,the extent of phenotypic changes are highly variable. Phenotypic effectsinduced by antisense effects are based on changes in criteria such asprotein levels, protein activity measurement, and target mRNA levels.Multidrug resistance is a useful model to study molecular eventsassociated with phenotypic changes due to antisense effects, since themultidrug resistance phenotype can be established by expression of asingle gene mdr1(MDR gene) encoding for P-glycoprotein.

Transplantation of normal genes into the affected area of the patientcan also be useful therapy for Alzheimer's Disease. In this procedure, anormal human PS1 gene is transferred into a cultivatable cell type suchas glial cells, either exogenously or endogenously to the patient. Thesecells are then injected serotologically into the disease-affected tissueor tissues. This is a known treatment for Parkinson's disease.

Similar gene therapy strategies may be employed with respect to the PS2gene in patients suffering from abnormalities in this gene.

Immunotherapy is also possible for Alzheimer's Disease. Antibodies areraised to a mutant PS1 or PS2 protein (or a portion thereof) and areadministered to the patient to bind or block the mutant protein andprevent its deleterious effects. Simultaneously, expression of thenormal protein product could be encouraged. Alternatively, antibodiesare raised to specific complexes between mutant or wild-type PS1 or PS2and their interaction partners.

A further approach is to stimulate endogenous antibody production to thedesired antigen. Administration could be in the form of a one timeimmunogenic preparation or vaccine immunization. An immunogeniccomposition may be prepared as injectables, as liquid solutions oremulsions. The PS1 or PS2 protein or other antigen may be mixed withpharmaceutically acceptable excipients compatible with the protein. Suchexcipients may include water, saline, dextrose, glycerol, ethanol andcombinations thereof. The immunogenic composition and vaccine mayfurther contain auxiliary substances such as emulsifying agents oradjuvants to enhance effectiveness. Immunogenic compositions andvaccines may be administered parenterally by injection subcutaneously orintramuscularly.

The immunogenic preparations and vaccines are administered in suchamount as will be therapeutically effective, protective and immunogenic.Dosage depends on the route of administration and will vary according tothe size of the host.

The above disclosure generally describes the present invention. A morecomplete understanding can be obtained by reference to the followingspecific examples. These examples are described solely for purposes ofillustration and are not intended to limit the scope of the invention.Changes in the form and substitution of equivalents are contemplated ascircumstances may suggest or render expedient. Although specific termshave been employed herein, such terms are intended in a descriptivesense and not for purposes of limitation.

The examples are described for the purposes of illustration and are notintended to limit the scope of the invention.

EXAMPLES Example 1

Development of the genetic, physical "contig" and transcriptional map ofthe minimal co-segregating region

The CEPH MegaYAC and the RPCI PAC human total genomic DNA libraries weresearched for clones containing genomic DNA fragments from the AD3 regionof chromosome 14q24.3 using oligonucleotide probes for each of the 12SSR marker loci used in the genetic linkage studies as well as theadditional markers depicted in FIG. 1A (Albertsen et al., 1990; Chumakovet al., 1992; Ioannu et al., 1994). The genetic map distances betweeneach marker are depicted above the contig, and are derived frompublished data (NIH/CEPH Collaborative Mapping Group, 1992; Wang, 1992;Weissenbach, J et al., 1992; Gyapay, G et al., 1994). Clones recoveredfor each of the initial marker loci were arranged into an ordered seriesof partially overlapping clones ("contig") using four independentmethods. First, sequences representing the ends of the YAC insert wereisolated by inverse PCR (Riley et al., 1990), and hybridized to Southernblot panels containing restriction digests of DNA from all of the YACclones recovered for all of the initial loci in order to identify otherYAC clones bearing overlapping sequences. Second, inter-Alu PCR wasperformed on each YAC, and the resultant band patterns were comparedacross the pool of recovered YAC clones in order to identify otherclones bearing overlapping sequences (Bellamne-Chartelot et al., 1992;Chumakov et al., 1992). Third, to improve the specificity of the Alu-PCRfingerprinting, the YAC DNA was restricted with HaeIII or RsaI, therestriction products were amplified with both Alu and L1H consensusprimers, and the products were resolved by polyacrylamide gelelectrophoresis. Finally, as additional STSs were generated during thesearch for transcribed sequences, these STSs were also used to identifyoverlaps. The resultant contig was complete except for a singlediscontinuity between YAC932C7 bearing D14S53 and YAC746B4 containingD14S61. The physical map order of the STSs within the contig was largelyin accordance with the genetic linkage map for this region (NIH/CEPHCollaborative Mapping Group, 1992; Wang, Z, Weber, J. L., 1992;Weissenbach, J et al., 1992; Gyapay, G et al., 1994). However, as withthe genetic maps, it was not possible to resolve unambiguously therelative order of the loci within the D14S43/D14S71 cluster and theD14S76/D14S273 cluster. PAC1 clones suggested that D14S277 is telomericto D14S268, whereas genetic maps have suggested the reverse order.Furthermore, a few STS probes failed to detect hybridization patterns inat least one YAC clone which, on the basis of the most parsimoniousconsensus physical map and from the genetic map, would have beenpredicted to contain that STS. For instance, the D14S268 (AFM265) andRSCAT7 STSs are absent from YAC788H12. Because these results werereproducible, and occurred with several different STS markers, theseresults most likely reflect the presence of small interstitial deletionswithin one of the YAC clones.

Example 2

Cumulative two-point lod scores for chromosome 14q24.3 markers.

Genotypes at each polymorphic microsatellite marker locus weredetermined by PCR from 100 ng of genomic DNA of all available affectedand unaffected pedigree members as previously described (StGeorge-Hyslop, P et al., 1992) using primer sequences specific for eachmicrosatellite locus (Weissenbach, J et al., 1992; Gyapay, G et al.,1994). The normal population frequency of each allele was determinedusing spouses and other neurologically normal subjects from the sameethnic groups, but did not differ significantly from those establishedfor mixed Caucasian populations (Weissenbach, J et al., 1992; Gyapay, Get al., 1994). The maximum likelihood calculations assumed an age ofonset correction, marker allele frequencies derived from publishedseries of mixed Caucasian subjects, and an estimated allele frequencyfor the AD3 mutation of 1:1000 as previously described (StGeorge-Hyslop, P et al., 1992). The analyses were repeated using equalmarker allele frequencies, and using phenotype information only fromaffected pedigree members as previously described to ensure thatinaccuracies in the estimated parameters used in the maximum likelihoodcalculations did not misdirect the analyses (St George-Hyslop, P et al.,1992). These supplemental analyses did not significantly alter eitherthe evidence supporting linkage, or the discovery of recombinationevents.

Example 3

Haplotypes between flanking markers segregated with AD3 in FAD pedigrees

Extended haplotypes between the centromeric and telomeric flankingmarkers on the parental copy of chromosome 14 segregating with AD3 infourteen early onset FAD pedigrees (pedigrees NIH2, MGH1, Tor1.1, FAD4,FAD1, MEX1, and FAD2 show pedigree specific lod scores ≧+3.00 with atleast one marker between D14S258 and D14S53). Identical partialhaplotypes (boxed) are observed in two regions of the disease bearingchromosome segregating in several pedigrees of similar ethnic origin. Inregion A, shared alleles are seen at D14S268 ("B": allele size=126 bp,allele frequency in normal Caucasians=0.04; "C": size=124 bp,frequency=0.38); D14S277 ("B": size=156 bp, frequency=0.19; "C":size=154 bp, frequency=0.33); and RSCAT6 ("D": size=111 bp, frequency0.25; "E": size=109 bp, frequency=0.20; "F": size=107 bp,frequency=0.47). In region B, alleles of identical size are observed atD14S43 ("A": size=193 bp, frequency=0.01; "D": size=187 bp,frequency=0.12; "E": size=185 bp, frequency=0.26; "I": size=160 bp,frequency=0.38); D14S273 ("3": size=193 bp, frequency=0.38; "4" size=191bp, frequency=0.16; "5": size=189 bp, frequency=0.34; "6": size=187 bp,frequency=0.02) and D14S76 ("1": size=bp, frequency=0.01; "5": size=bp,frequency=0.38; "6": size=bp, frequency=0.07; "9": size=bp,frequency=0.38). The ethnic origins of each pedigree are abbreviated as:Ashk=Ashkenazi Jewish; Ital=Southern Italian; Angl=Anglo-Saxon-Celt;FrCan=French Canadian; Jpn=Japanese; Mex=Mexican Caucasian; Ger=German;Am=American Caucasian. The type of mutation detected is depicted by theamino acid substitution and putative codon number or by ND where nomutation has been detected because a comprehensive survey has not beenundertaken due to the absence of a source of mRNA for RT-PCR studies.

Example 4

Recovery of transcribed sequences from the AD3 interval.

Putative transcribed sequences encoded in the AD3 interval wererecovered using a direct hybridization method in which short cDNAfragments generated from human brain mRNA were hybridized to immobilizedcloned genomic DNA fragments (Rommens, J M et al., 1993). The resultantshort putatively transcribed sequences were used as probes to recoverlonger transcripts from human brain cDNA libraries (Stratagene, LaJolla). The physical locations of the original short clone and of thesubsequently acquired longer cDNA clones were established by analysis ofthe hybridization pattern generated by hybridizing the probe to Southernblots containing a panel of EcoRI digested total DNA samples isolatedfrom individual YAC clones within the contig. The nucleotide sequence ofeach of the longer cDNA clones was determined by automated cyclesequencing (Applied Biosystems Inc., Calif.), and compared to othersequences in nucleotide and protein databases using the blast algorithm(Altschul, S F et al., 1990). Accession numbers for the transcribedsequences in this report are: L4039 1, L40392, L40393, L40394, L40395,L40396,L40397, L40398, L40399,L40400, L40401,L40402, and L40403.

Example 5

Locating mutations in the ARMP (PS1) gene using restriction enzymes.

The presence of Ala246Glu mutation which creates a Dde1 restriction sitewas assayed in genomic DNA by PCR using the end labelled primer(5'-ATCTCCGGCAGGCATATCT-3') SEQ ID NO:129 and the unlabelled primer(5'-TGAAATCACAGCCAAGATGAG-3') SEQ ID NO:130 to amplify an 84 bp genomicexon fragment using 100 ng of genomic DNA template, 2 mM MgCl₂, 10pMoles of each primer, 0.5U Taq polymerase, 250 uM dNTPs for 30 cyclesof 95° C.×20 seconds, 60° C.×20 seconds, 72° C.×5 seconds. The productswere incubated with an excess of DdeI for 2 hours according to themanufacturers protocol, and the resulting restriction fragments wereresolved on a 6% nondenaturing polyacrylamide gel and visualized byautoradiography. The presence of the mutation was inferred from thecleavage of the 84 bp fragment to due to the presence of a DdeIrestriction site. All affected members of the FAD1 pedigree (filledsymbols) and several at risk members ("R") carried the DdeI site. Noneof the obligate escapees (those individuals who do not get the disease,age >70years), and none of the normal controls carried the DdeImutation.

Example 6

Locating mutations in the ARMP (PS1) gene using allele specificoligonucleotides.

The presence of the Cys 410 Tyr mutation was assayed using allelespecific oligonucleotides. 100 ng of genomic DNA was amplified with theexonic sequence primer (5'-TGGAGACTGGAACACAAC-3') SEQ ID NO:127 and theopposing intronic sequence primer (5'-GTGTGGCCAGGGTAGAGAACT-3') SEQ IDNO:128 using the above reaction conditions except 2.5 mM MgCl₂, andcycle conditions of 94° C.×20 seconds, 58° C.×20 seconds, and 72° C. for10 seconds). The resultant 216 bp genomic fragment was denatured by10-fold dilution in 0.4M NaOH, 25 mM EDTA, and was vacuum slot-blottedto duplicate nylon membranes. The end-labelled "wild type" primer(5'-CCATAGCCTGTTTCGTAGC-3') Seq ID NO:131 and the end-labelled "mutant"primer (5'-CCATAGCCTATTTCGTAGC-3') SEQ ID No:132 were hybridized toseparate copies of the slot-blot filters in 5×SSC, 5×Denhardt's, 0.5%SDS for 1 hour at 48° C., and then washed successively in 2×SSC at 23°C. and 2×SSC, 0.1% SDS at 50° C. and then exposed to X-ray film. Alltestable affected members as well as some at-risk members of the AD3 andNIH2 pedigrees possessed the Cys 410 Tyr mutation. Attempts to detectthe Cys 410 Tyr mutation by SSCP revealed that a common intronicsequence polymorphism migrated with the same SSCP pattern.

Example 7

Northern hybridization demonstrating the expression of ARMP (PS1)protein mRNA in a variety of tissues.

Total cytoplasmic RNA was isolated from various tissue samples(including heart, brain and different regions of, placenta, lung, liver,skeletal muscle, kidney and pancreas) obtained from surgical pathologyusing standard procedures such as CsCl purification. The RNA was thenelectrophoresed on a formaldehyde gel to permit size fractionation. Thenitrocellulose membrane was prepared and the RNA was then transferredonto the membrane. ³² P-labelled cDNA probes were prepared and added tothe membrane in order for hybridization between the probe the RNA tooccur. After washing, the membrane was wrapped in plastic film andplaced into imaging cassettes containing X-ray film. The autoradiographswere then allowed to develop for one to several days. Sizing wasestablished by comparison to standard RNA markers. Analysis of theautoradiographs revealed a prominent band at 3.0 kb in size. Thesenorthern blots demonstrated that the ARMP gene is expressed in all ofthe tissues examined.

Example 8

Eukaryotic and Prokaryotic Expression Vector Systems

Constructs suitable for use in eukaryotic and prokaryotic expressionsystems have been generated using two different classes of ARMPnucleotide cDNA sequence inserts. In the first class, termed full-lengthconstructs, the entire ARMP cDNA sequence is inserted into theexpression plasmid in the correct orientation, and includes both thenatural 5' UTR and 3' UTR sequences as well as the entire open readingframe. The open reading frames bear a nucleotide sequence cassette whichallows either the wild type open reading frame to be included in theexpression system or alternatively, single or a combination of doublemutations can be inserted into the open reading frame. This wasaccomplished by removing a restriction fragment from the wild type openreading frame using the enzymes NarI and PflmI and replacing it with asimilar fragment generated by reverse transcriptase PCR and bearing thenucleotide sequence encoding either the Met146Leu mutation or theHys163Arg mutation. A second restriction fragment was removed from thewild type normal nucleotide sequence for the open reading frame bycleavage with the enzymes PflmI and NcoI and replaced with a restrictionfragment bearing the nucleotide sequence encoding the Ala246Glumutation, the Ala260Val mutation, the Ala285Val mutation, the Leu286Valmutation, the Leu392Val mutation or the Cys410Tyr mutation. A thirdvariant, bearing a combination of either the Met146Leu or His163Argmutation in tandem with one of the remaining mutations, was made bylinking a NarI-PflmI fragment bearing one of the former mutations and aPflmI-NcoI fragment bearing one of the latter mutations.

The second class of cDNA inserts, termed truncated constructs, wasconstructed by removing the 5' UTR and part of the 3' UTR sequences fromfull length wild type or mutant cDNA sequences. The 5' UTR sequence wasreplaced with a synthetic oligonucleotide containing a KpnI restrictionsite and a Kozak initiation site (oligonucleotideGGTACCGCCACCATGACAGAGGTACCTGCAC, SEQ ID NO:139). The 3' UTR was replacedwith an oligonucleotide corresponding to position 2566 of the cDNA andbore an artificial EcoRI site (oligonucleotideGAATTCACTGGCTGTAGAAAAAGAC, SEQ ID NO:140). Mutant variants of thisconstruct were then made by inserting the mutant sequences describedabove at the NarI-PflmI and PsImI-NcoI sites as described above.

For eukaryotic expression, these various cDNA constructs bearing wildtype and mutant sequences, as described above, were cloned into theexpression vector pZeoSV in which the SV60 promoter cassette had beenremoved by restriction digestion and replaced with the CMV promoterelement of pcDNA3 (Invitrogen). For prokaryotic expression, constructshave been made using the glutathione S-transferase (GST) fusion vectorpGEX-kg. The inserts which have been attached to the GST fusionnucleotide sequence are the same nucleotide sequences described above(generated with the oligonucleotide primers, SEQ ID NO:139 and SEQ IDNO:140) bearing either the normal open reading frame nucleotidesequence, or bearing a combination of single and double mutations asdescribed above. These GST fusion constructs allow expression of thepartial or full-length protein in prokaryotic cell systems as mutant orwild type GST fusion proteins, thus allowing purification of thefull-length protein followed by removal of the GST fusion product bythrombin digestion. A further cDNA construct was made with the GSTfusion vector, to allow the production of the amino acid sequencecorresponding to the hydrophilic acidic loop domain between TM6 and TM7of the full-length protein, either as a wild type nucleotide sequence oras a mutant sequence bearing either the Ala285Val mutation, theLeu286Val mutation or the Leu392Val mutation. This was accomplished byrecovering wild type or mutant sequence from appropriate sources of RNAusing the oligonucleotide primers GGATCCGGTCCACTTCGTATGCTG, SEQ IDNO:141, and TTTTTTGAATTCTTAGGCTATGGTTGTGTTCCA, SEQ ID NO:142 Thisallowed cloning of the appropriate mutant or wild type nucleotidesequence corresponding to the hydrophilic acidic loop domain at theBamHI and the EcoRI sites within the pGEX-KG vector.

Example 9

Locating additional mutations in the ARMP (PS1) gene

Mutations in the ARMP (PS1) gene can be assayed by a variety ofstrategies (direct nucleotide sequencing, allele specific oligos,ligation polymerase chain reaction, SSCP, RFLPs) using RT-PCR productsrepresenting the mature mRNA/cDNA sequence or genomic DNA. For the A260Vand the A285V mutations, genomic DNA carrying the exon can be amplifiedusing the same PCR primers and methods as for the L286V mutation.

PCR products were then denatured and slot blotted to duplicate nylonmembranes using the slot blot protocol described for the C410T mutation.

The Ala260Val mutation was scored on these blots by using hybridizationwith end-labelled allele-specific oligonucleotides corresponding to thewild type sequence (GATTAGTGGTTGTTTTGTG) SEQ ID NO:143 or the mutantsequence (GATTAGTGGCTGTTTTGTG) SEQ ID NO:144 by hybridization at 48° C.followed by a wash at 52° C. in 3×SSC buffer containing 0.1 % SDS. TheAla285Val mutation was scored on these slot blots as described above butusing instead the allele-specific oligonucleotides for the wild typesequence (TTTTTCCAGCTCTCATTTA) SEQ ID NO:145 or the mutant primer(TTTTTCCAGTTCTCATTTA) SEQ ID NO:146 at 48° C. followed by washing at 52°C. as above except that the wash solution was 2×SSC.

The Leu392Val mutation was scored by amplification of the exon fromgenomic DNA using primers (AAACTTGGATTGGGAGAT) SEQ ID NO:148 and(GTGTGGCCAGGGTAGAGAACT) SEQ ID NO:128 using standard PCR bufferconditions except that the magnesium concentration was 2 mM and cycleconditions were 94° C. time 10 seconds, 56° C. times 20 seconds, and 72°C. for 10 seconds. The resulting 200 base pair genomic fragment wasdenatured as described for the Cys410Tyr mutation and slot-blotted induplicate to nylon membranes. The presence or absence of the mutationwas then scored by differential hybridization to either a wild typeend-labelled oligonucleotide (TACAGTGTTCTGGTTGGTA) SEQ ID NO:147 or withan end-labelled mutant primer (TACAGTGTTGTGGTTGGTA) SEQ ID NO:149 byhybridization at 45° C. and then successive washing in 2×SSC at 23° C.and then at 68° C.

Example 10

Antibody Production

Peptide antigens corresponding to portions of the PS1 protein weresynthesized by solid-phase techniques and purified by reverse phase highpressure liquid chromatography. Peptides were covalently linked tokeyhole limpet hemocyanin (KLH) via disulfide linkages that were madepossible by the addition of a cysteine residue at the peptideC-terminus. This additional residue does not appear normally in theprotein sequence and was included only to facilitate linkage to the KLHmolecule.

The specific sequences to which antibodies were raised are as follows:

Polyclonal antibody 1142: NDNRERQEHNDRRSL (C)-residues 30-45 (Seq IDNO:167);

Polyclonal antibody 519: KDGQLIYTPFTEDTE (C)-residues 109-120 (Seq IDNO:168);

Polyclonal antibody 520: EAQRRVSKNSKYNAE (C)-residues 304-319 (Seq IDNO:169);

Polyclonal antibody 1143: SHLGPHRSTPESRAA (C)-residues 346-360 (Seq IDNO:170).

The non-native cysteine residue is indicated at the C-terminal by (C).These sequences are contained within specific unique domains of the PS1protein. For example, sequences 167, 169 and 170 are located inpotentially functional domains that are exposed to the aqueous media andmay be involved in binding to other proteins critical for thedevelopment of the disease phenotype. Sequence 168 corresponds to ashort linking region situated between the predicted first and secondtransmembrane helices. The choice of peptides was based on analysis ofthe protein sequence using the IBI Pustell antigenicity predictionalgorithm.

A total of three New Zealand white rabbits were immunized withpeptide-KLH complexes for each peptide antigen in combination withFreund's adjuvant and were subsequently given booster injections atseven day intervals. Antisera were collected for each peptide and pooledand IgG precipitated with ammonium sulfate. Antibodies were thenaffinity purified with Sulfo-link agarose (Pierce) coupled with theappropriate peptide. This final purification is required to removenon-specific interactions of other antibodies present in either the pre-or post-immune serum.

The specificity of each antibody was confirmed by three tests. First,each detected single predominant bands of the approximate size predictedfor presenilin I on Western blots of brain homogenate. Second, eachcross-reacted with recombinant fusion proteins bearing the appropriatesequence. Third each could be specifically blocked by pre-absorptionwith recombinant PS1 or the immunizing peptide.

In addition, two different PS1 peptide glutathione S-transferase (GST)fusion proteins have been used to generate PS1 antibodies. The firstfusion protein included amino acids 1-81 (N terminus) of PS1 fused toGST. The second fusion protein included amino acids 266-410 (the TM6-TM7loop domain) of PS1 fused to GST. Constructs encoding these fusionproteins were generated by inserting the appropriate nucleotidesequences into pGEX-2T expression plasmid (Amrad). The resultingconstructs included sequences encoding GST and a site for thrombinsensitive cleavage between GST and the PS1 peptide. The expressionconstructs were transfected into DH5α E. coli and expression of thefusion proteins was induced using IPTG. The bacterial pellets were lysedand the soluble GST-fusion proteins were purified by single stepaffinity chromatography on glutathione sepharose beads(Boehringer-Mannheim, Montreal). The GST-fusion proteins were used toimmunize mice to generate monoclonal antibodies using standardprocedures. Clones obtained from these mice were screened with purifiedpresenilin fragments.

In addition, the GST-fusion proteins were cleaved with thrombin torelease PS1 peptide. The released peptides were purified by sizeexclusion HPLC and used to immunize rabbits for the generation ofpolyclonal antisera.

By similar methods, GST fusion proteins were made using constructsincluding nucleotide sequences for amino acids 1 to 87 (N terminus) or272 to 390 (TM6→TM7 loop) of presenilin II and employed to generatemonoclonal antibodies to that protein. The PS2 GST fusion proteins werealso cleaved with thrombin and the released, purified peptides used toimmunize rabbits to prepare polyclonal antisera.

Example 11

Identification of mutations in E5-1 (PS2) gene

RT-PCR products corresponding to the E5-1 (PS2) ORF were generated fromRNA of lymphoblasts or frozen post-mortem brain tissue usingoligonucleotide primer pairs 5'-CAGAGGATGGAGAGAATAC (SEQ ID NO:: 171)and 5'-GGCTCCCCAAAACTGTCAT (SEQ ID NO:: 172) (product=888 bp); and5'-GCCCTAGTGTTCATCAAGTA (SEQ ID NO:: 173) and 5'-AAAGCGGGAGCCAAAGTC (SEQID NO:: 174) (product=826 bp) by PCR using 250 μMol dNTPs, 2.5 mM MgCl2,10 pMol oligonucleotides in 10 μl cycled for 40 cycles of 94° C.×20seconds, 58° C.×20 seconds, 72° C.×45 seconds. The PCR products weresequenced by automated cycle sequencing (ABI, Foster City, A) and thefluorescent chromatograms were scanned for heterozygous nucleotidesubstitutions by direct inspection and by the Factura (ver 1.2.0) andSequence Navigator (ver 1.0.1b15) software packages (data not shown).

Asn141Ile: The A→T substitution at nucleotide 787 creates a BclIrestriction site. The exon bearing this mutation was amplified from 100ng of genomic DNA using 10 pMol of oligonucleotides5'-CATTCACTGAGGACACACC (SEQ ID NO:175) (end-labelled) and5'-TGTAGAGCACCACCAAGA (SEQ ID NO:176) (unlabelled), and PCR reactionconditions similar to those described below for the Met239Val. 2 μl ofthe PCR product was restricted with BclI (NEBL, Beverly, Mass.) in 10 μlreaction volume according to the manufacturers' protocol, and theproducts were resolved by non-denaturing polyacrylamide gelelectrophoresis. In subjects with wild type sequences, the 114 bp PCRproduct is cleaved into 68 bp and 46 bp fragments. Mutant sequencescause the product to be cleaved into 53 bp, 46 bp and 15 bp.

Met239Val: The A→G substitution at nucleotide 1080 deletes a NlaIIIrestriction site, allowing the presence of the Met239Val mutation to bedetected by amplification from 100 ng of genomic DNA using PCR (10 pMololigonucleotides 5'-GCATGGTGTGCATCCACT (SEQ ID NO:: 177),5'-GGACCACTCTGGGAGGTA (SEQ ID NO:: 178); 0.5 U Taq polymerase, 250 μMdNTPS, 1 μCi alpha ³² P-dCTP, 1.5 mM MgCl₂, 10 μl volume; 30 cycles of94° C.×30 seconds, 58° C.×20 seconds, 72° C.×20 seconds) to generate a110 bp product. 2 μl of the PCR reaction were diluted to 10 μl andrestricted with 3 U of NlaIII (NEBL, Beverly, Mass.) for 3 hours. Therestriction products were resolved by non-denaturing polyacrylamide gelelectrophoresis and visualized by autoradiography. Normal subjects showcleavage products of 55, 35, 15 and 6 bp, whereas the mutant sequencegives fragments of 55, 50 and 6 bp.

In accordance with a further embodiment, the Ile 420 Thr mutation isscreened for by PCR amplification of genomic DNA using primers 5' TGCTGC TTG CTG TGT TCA 3' (SEQ ID NO:161) and 5' CCA TGT CCC TCA GAT GTA GA3' (SEQ ID NO:162) to generate a 146 base pair product which can beprobed with allele specific oligonucleotides for the wild-type (5' CATCTC CAT CAC GTT CG 3'; SEQ ID NO:163) and mutant (5' CAT CTC CAC CAC GTTCG 3'; SEQ ID NO:164) sequences.

Example 12

Transgenic Mice

A series of wild type and mutant PS1 and PS2 genes were constructed foruse in the preparation of transgenic mice. Mutant versions of PS1 andPS2 were generated by site-directed mutagenesis of the cloned cDNAs CC33(PS1) and CC32 (PS2) using standard techniques.

cDNAs CC33 and CC32 and their mutant versions were used to prepare twoclasses of mutant and wild type PS1 and PS2 cDNAs, as described inExample 8. The first class, referred to as "full-length" cDNAs, wereprepared by removing approximately 200 bp of the 3' untranslated regionimmediately before the poly A site by digestion with EcoRI (PS1) orPvuII (PS2). The second class, referred to as "truncated" cDNAs, wereprepared by replacing the 5' untranslated region with a ribosome bindingsite (Kozak consensus sequence) placed immediately 5' of the ATG startcodon.

Various full length and truncated wild type and mutant PS1 and PS2cDNAs, prepared as described above, were introduced into one or more ofthe following vectors and the resulting constructs were used as a sourceof gene for the production of transgenic mice.

The cos.TET expression vector: This vector was derived from a cosmidclone containing the Syrian hamster PrP gene. It has been described indetail by Scott et al. (1992) and Hsiao et al. (1995). PS1 and PS2 cDNAs(full length or truncated) were inserted into this vector at its SalIsite. The final constructs contain 20 kB of 5' sequence flanking theinserted cDNA. This 5' flanking sequence includes the PrP gene promoter,50 bp of a PrP gene 5' untranslated region exon, a splice donor site, a1 kB intron, and a splice acceptor site located immediately adjacent tothe SalI site into which the PS1 or PS2 cDNA was inserted. The 3'sequence flanking the inserted cDNA includes an approximately 8 kBsegment of PrP 3' untranslated region including a polyadenylationsignal. Digestion of this construct with NotI (PS1) or FseI (PS2)released a fragment containing a mutant or wild type PS gene under thecontrol of the PrP promoter. The released fragment was gel purified andinjected into the pronuclei of fertilized mouse eggs using the method ofHsiao et al., 1995 (Table 12).

Platelet-derived growth factor receptor β-subunit constructs: PS cDNAswere also introduced between the SalI (full length PS1 cDNAs) or HindIII(truncated PS1 cDNAs, full length PS2 cDNAs, and truncated PS2 cDNAs) atthe 3' end of the human platelet derived growth factor receptorβ-subunit promoter and the EcoRI site at the 5' end of the SV40 poly Asequence and the entire cassette was cloned into the pZeoSV vector(Invitrogen, San Diego, Calif.). Fragments released by ScaI/BamHIdigestion were gel purified and injected into the pronuclei offertilized mouse eggs using the method of Hsiao et al. (supra) (Table12).

Human β-actin constructs: Certain PS1 and PS2 cDNAs were inserted intothe SalI site of pBAcGH. The construct produced by this insertionincludes 3.4 kB of the human β actin 5' flanking sequence (the human βactin promoter, a spliced 78 bp human β actin 5' untranslated exon andintron) and the PS1 or PS2 insert followed by 2.2 kB of human growthhormone genomic sequence containing several introns and exons as well asa polyadenylation signal. SfiI was used to release a PS-containingfragment which was gel purified and injected into the pronuclei offertilized mouse eggs using the method of Hsiao et al. (supra) (Table12).

Phosphoglycerate kinase constructs: Certain PS1 and PS2 cDNAs wereintroduced into the pkJ90 vector. The cDNAs were inserted between theKpnI site downstream of the human phosphoglycerate kinase promoter andthe XbaI site upstream of the 3' untranslated region of the humanphosphoglycerate kinase gene. PvuII/HindIII (PS1 cDNAs) or PvuII (PS2cDNAs) digestion was used to release a PS-containing fragment which wasthen gel purified and injected into the pronuclei of fertilized mouseeggs as described above.

Table 10 includes a summary of the preparation of transgenic mice.

Example 13

Expression of Recombinant PS1 and PS2 in Eukaryotic Cells

Recombinant PS1 and PS2 have been expressed in a variety of cell types(e.g. PC12, neuroblastoma, Chinese hamster ovary, and human embryonickidney 293 cells) using the pcDNA3 vector (Invitrogen, San Diego,Calif.). The PS1 and PS2 cDNAs inserted into this vector were the samefull length and truncated cDNAs described in Example 8.

These cDNAs were inserted between the CMV promoter and the bovine growthhormone polyadenylation site of pcDNA3. The transgenes were expressed athigh levels.

In addition, PS1 and PS2 have been expressed in COS cells using the pCMXvector. To facilitate tagging and tracing of the intracellularlocalization of the presenilin proteins, oligonucleotides encoding an 11amino acid sequence derived from c-myc (EQKLISEEDLN; SEQ ID NO:183) andrecognized by the monoclonal anti-MYC antibody 9E10.2 (ATCC, Rockville,Md.) were ligated in-frame either immediately in front or immediatelybehind the open reading frame of PS1 and PS2 cDNAs. Untagged pCMXconstructs were also prepared. The c-myc-tagged constructs were alsointroduced into pcDNA3 for transfection into CHO cells.

Transient and stable transfection of these constructs has been achievedusing Lipofectamine (Gibco/BRL) according to the manufacturer'sprotocols. Cultures were assayed for transient expression after 48hours. Stably transfected lines were selected using 0.5 mg/ml Geneticin(Gibco/BRL).

Expression of transfected PS proteins was assayed by Western blot usingthe anti-presenilin antibodies 1142, 519 and 520 described above.Briefly, cultured transfected cells were solubilized (2% SDS, 5 mM EDTA,1 mg/ml leupeptin and aprotinin), and the protein concentration wasdetermined by Lowry. Proteins were separated on SDS-PAGE gradient gels(4-20% Novex) and transferred to PVDF (10 mM CAPS) for 2 hr at aconstant voltage (50V). Non-specific binding was blocked with skim milk(5%) for 1 hr. The proteins were then probed with the two rabbitpolyclonal antibodies (˜1 mg/ml in TBS, pH 7.4) for 12 hrs. Presenilincross-reactive species were identified using biotinylated goat-antirabbit secondary antibody which was visualized using horseradishperoxidase-conjugated strepavadin tertiary, 4-chloro-napthol, andhydrogen peroxide. The c-myc-tagged presenilin peptides were assayed byWestern blotting using both the anti-presenilin antibodies describedabove (to detect the presenilin peptide antigen), and culturesupernatant from the hybridoma MYC1-9E10.2 (ATCC) diluted 1:10 forwestern blots and 1:3 for immunocytochemistry (to detect themyc-epitope). A major band of immunoreactivity of 50-60 kDa wasidentified by each of the various presenilin antibodies, and by themyc-epitope antibodies (for cell lines transfected with myc-containingplasmids). Minor bands at ˜10-19 kDa and at ˜70 kDa were detected bysome presenilin antibodies.

For immunocytochemistry, transfected cells were fixed with 4%formaldehyde in TRIS buffered saline (TBS), washed extensively with TBSplus 0.1% Triton and non-specific binding blocked with 3% BSA. Fixedcells were probed with the presenilin antibodies (e.g. LL520 and SN1142;typically 5-10 mg/ml), washed and visualized with FITC- orrhodamine-conjugated goat-anti rabbit secondary antibody. Forc-myc-tagged presenilin constructs, the hybridoma MYC1-9E10.2 (ATCC)supernatant diluted 1:3 was used with anti-mouse secondary antibody.Slides were mounted in 90% glycerol with 0.1% phenylenediamine (ICN) topreserve fluorescence. Anti-BIP (or anti-calnexin) (StressGen, Victoria,B.C.) and wheat germ agglutinin (EY Labs, San Mateo, Calif.) were used amarkers of endoplasmic reticulum and Golgi respectively.Double-immuno-labelling was also performed with anti-actin (Sigma, St.Louis, Mo.), anti-amyloid precursor protein (22C11, Boehringer Mannheim)and anti-neurofilament (NF-M specific, Sigma) in neuronal line NSC34.These immunofluorescence studies demonstrated that the transfectionproduct is widely distributed within the cell, with a particularlyintense perinuclear localization suggestive of endoplasmic reticulum andGolgi, which is similar to that observed in untransfected cells but ismore intense, sometimes spilling over into the nuclear membrane.Co-immunolocalization of the c-myc and PS epitopes was observed in CHOand COS cells transiently transfected with the myc-tagged presenilinconstructs.

Robust expression of the transfected presenilin gene in the transfectedcells was thus proven by immunocytochemistry, Northern blot, Westernblots (using antibodies to presenilins as above, and using themonoclonal antibody MYC1-9E10.2 to the myc-tag in constructs with 3' or5' c-myc tags).

Example 14

Isolation of Presenilin Binding Proteins by Affinity Chromatography

To identify the proteins which may be involved in the biochemicalfunction of the presenilins, PS1 -binding proteins were isolated usingaffinity chromatography. A GST-fusion protein containing the PSI TM6-TM7loop, prepared as described in Example 8, was used to probe human brainextracts, prepared by homogenising brain tissue by Polytron inphysiological salt solution. Non-specific binding was eliminated bypre-clearing the brain homogenates of endogenous GST-binding componentsby incubation with glutathione-Sepharose beads. These GST-freehomogenates were then incubated with the GST-PS fusion proteins toproduce the desired complexes with functional binding proteins. Thesecomplexes were then recovered using the affinity glutathione-Sepharosebeads. After extensive washing with phosphate buffered saline, theisolated collection of proteins was separated by SDS-polyacrylamide gelelectrophoresis (SDS-PAGE; Tris-tricine gradient gel 4-20%). Two majorbands were observed at ˜14 and 20 kd in addition to several weaker bandsranging from 50 to 60 kd.

Pharmacologic modification of interaction between these proteins and theTM6-TM7 loop may be employed in the treatment of Alzheimer's Disease. Inaddition, these proteins which are likely to act within the presenilinbiochemical pathway may be novel sites of mutations that causeAlzheimer's Disease.

Example 15

Isolation of Presenilin Binding Proteins by Two-Hybrid Yeast System

To identify proteins interacting with the presenilin proteins, a yeastexpression plasmid vector (pAS2-1, Clontech) was generated by ligatingan in-frame partial cDNA sequence encoding either residues 266-409 ofthe PS1 protein or residues 272-390 of the PS2 protein into the EcoR1and BamHI sites of the vector. The resultant fusion protein contains theGAL4 DNA binding domain coupled in frame either to the TM6-TM7 loop ofthe PS1 protein or to the TM6-TM7 loop of the PS2 protein. Theseexpression plasmids were co-transformed, along with purified plasmid DNAfrom the human brain cDNA:pACT library, into yeast using the protocolsof the Clontech Matchmaker yeast-two-hybrid kit (Clontech). Yeast clonesbearing human brain cDNAs which interact with the TM6-TM7 loop domainwere selected by HIS resistance and βgal+activation. The clones werefurther selected by cyclohexamide sensitivity and the inserts of thehuman brain cDNAs were isolated by PCR and sequenced. Of 6 millioninitial transformants, 200 positive clones were obtained after HISselection, and 42 after βgal+colour selection, carried out in accordancewith the manufacturer's protocol for selection of positive colonies. Ofthese 42 clones there were several (5-8) independent clones representingthe genes typified by our clones pslly2h-9, pslly2h-6, and pslly2h-29.This indicates that these interactions are biologically real andreproducable.

Analysis of the sequences of these clones identified the proteins listedin Table 13 as interacting with the TM6-TM7 loop of PS1. The biologicrelevance of these interactions is described in the table. The effect ofmutations in the PS1 or PS2 gene on these interactions can be studiedand, by screening of chemical libraries, drugs which will modify theseinteractions positively or negatively can be identified. These compoundsare used to screen for effects in AD by analysis of changes in thefrequency and/or rate of development ofclinical/neuropathologic/biochemical changes of AD intransgenic/homologous recombination animal models or tissue culturemodels.

Example 16

Transgenic C. elegans

Transgenic C. elegans were obtained by microinjection of oocytes. Thevectors used and the transgenes inserted are shown in Table 11.Transformed animals were detected by assaying expression of human cDNAon northern blots or western blots using human cDNA probe CC32 andantibodies 519, 520 and 1142.

Example 17

Cloning of a Drosophila melanogaster homologue, DmPS, for the humanpresenilin genes

Redundant oligonucleotides 5'ctnccngartggacngyctgg (SEQ ID NO:179) and5'rcangc(agt)atngtngtrttcca (SEQ ID NO:180) were designed from publishednucleotide sequence data for highly conserved regions of thepresenilin/sel-12 proteins ending/beginning with Trp (e.g. at residuesTrp247 and Trp404 in PS1; Trp253 and Trp385 in PS2). These primers wereused for RT-PCR (50 μl volume, 2 mM MgCl₂, 30 cycles of 94° C.×30", 57°C.×20", 72° C.×20") from mRNA from adult and embryonic D. melanogaster.The products were then reamplified using cycle conditions of 94° C.×1',59° C.×0.5' and 72° C.×1' and internal conserved redundant primer5'ttttttctcgagacngcncargaragaaayga (SEQ ID NO::181) and5'ttttttggatcctaraa(agt)atraartcncc (SEQ ID NO:: 182). The ˜600 bpproduct was cloned into the BamHI and XhoI sites of pBS. These productswere sequenced and shown to contain an open reading frame with aputative amino acid sequence highly homologous to that of the humanpresenilins. This fragment was then used to screen a conventional D.melanogaster cDNA\zap library (Stratagene, Calif.) to recover sixindependent cDNA clones of size ˜2-2.5 kb (clones pds8, pds13, pds1,pds3, pds7 and pds14) which were sequenced. The longest ORF encodes apolypeptide of 541 amino acids with 52% identity to the humanpresenilins.

Although preferred embodiments of the invention have been describedherein in detail, it will be understood by those skilled in the art thatvariations may be made thereto without departing from the spirit of theinvention or the scope of the appended claims.

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                  TABLE 1                                                         ______________________________________                                        RECOMBINATION FRACTION (θ)                                              LOCUS  0.00    0.05   0.10   0.15 0.20   0.30 0.40                            ______________________________________                                        D14S63 -∞                                                                              1.54   3.90   4.38 4.13   2.71 1.08                            D14S258                                                                              -∞                                                                              21.60  19.64  17.19                                                                              14.50  8.87 3.81                            D14S77 -∞                                                                              15.18  15.53  14.35                                                                              12.50  7.82 2.92                            D14S71 -∞                                                                              15.63  14.14  12.19                                                                              10.10  5.98 2.39                            D14S43 -∞                                                                              19.36  17.51  15.27                                                                              12.84  7.80 3.11                            D14S273                                                                              -∞                                                                              12.30  11.52  10.12                                                                              8.48   5.04 1.91                            D14S61 -∞                                                                              26.90  24.92  22.14                                                                              18.98  12.05                                                                              5.07                            D14S53 -∞                                                                              11.52  11.41  10.39                                                                              8.99   5.73 2.51                            D14S48 -∞                                                                              0.50   1.05   1.14 1.04   0.60 0.18                            ______________________________________                                    

                                      TABLE 2                                     __________________________________________________________________________           PEDIGREE ID                                                            LOCUS  NIH2                                                                              FAD3                                                                              TUR1.1                                                                            FAD4                                                                              RB  FAD1                                                                              MG12                                                                              BOW COOK                                                                              683 Tor42                                                                             QUE MEX1                                                                              FAD2               __________________________________________________________________________    4 #STR1##                                                                            1 #STR2##                                                                             2 #STR3##                                                                                 3 #STR4##                                                                                     6 #STR5##                                                                                     9 #STR6##          ETHNIC Ashk                                                                              Ashk                                                                              Ital                                                                              Ital                                                                              Ital                                                                              Angl                                                                              Angl                                                                              Angl                                                                              Angl                                                                              Amer                                                                              FrCan                                                                             FrCan                                                                             Mex Ger                ORIGIN                                                                        MUTATION                                                                             C410Y                                                                             C410Y                                                                             M146L                                                                             M146L                                                                             ND  A246E                                                                             ND  ND  ND  H163R                                                                             H163R                                                                             ND  ND  L286V              __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________    DNASIS                                                                        Simple Homology Region [armp.con[Frame 1]]                                                                          SIMILARITIES                            No.                                                                              Target File     Key                                                                              Target                                                                             Overlap                                                                             Match                                                                              Percentage                              1  marmp.con/long[Frame 1]                                                                       1  1    467   465  99.57%                                  __________________________________________________________________________             1       10        20        30        40        50        60            70                                                                         HUMAN N- MTELPAPLSYFQNAQMSEDNHLSNTVRSQNDNRERQEHNDRRSLGHPEPLSNGRPQGNSRQVVEQ    DEEED                                                                                  *****************************************************************    *****                                                                         MOUSE N- MTEIPAPLSYFQNAQMSEDSHSSSAIRSQNDSQERQQQHDRQRLDNPEPISNGRPQSNSRQVVEQ    DEEED                                                                                  1       10        20        30        40        50        60            70                                                                                 71       80        90       100       110       120       130           140                                                                                  EELTLKYGAKHVIMLFVPVTLCMVVVVATIKSVSFYTRKDGQLIYTPFTEDTETVGQRALHSILN    AAIMI                                                                                  *****************************************************************    *****                                                                                  EELTLKYGAKHVIMLFVPVTLCMVVVVATIKSVSFYTRKDGQLIYTPFTEDTETVGQRALHSILN    AAIMI                                                                                 71       80        90       100       110       120       130           140                                                                                141      150       160       170       180       190       200           210                                                                                  SVIVVMTILLVVLYKYRCYKVIHAWLIISSLLLLFFFSFIYLGEVFKTYNVAVDYITVALLIWNL    GVVGM                                                                                  *****************************************************************    *****                                                                                  SVIVIMTILLVVLYKYRCYKVIHAWLIISSLLLLFFFSFIYLGEVFKTYNVXVDYVTVALLIWNW    GVVGM                                                                                141      150       160       170       180       190       200           210                                                                                211      220       230       240       250       260       270           280                                                                                  ISIHWKGPLRLQQAYLIMISALMALVFIKYLPEWTAWLILAVISVYDLVAVLCPKGPLRMLVETA    QERNE                                                                                  *****************************************************************    *****                                                                                  IAIHWKGPLRLQQAYLIMISALMALVFIKYLPEWTAWLILAVISVYDLVAVLCPKGPLRMLVETA    QERNE                                                                                211      220       230       240       250       260       270           280                                                                                281      290       300       310       320       330       340           350                                                                                  TLFPALTYSSTMVWLVNMAEGDPEAQRRVSKNSKYNAESTERESQDTVAENDDGGFSEEWEAQRD    SHLGP                                                                                  ***************************** ** ********************************    *****                                                                                  TLFPALTYSSTMVWLVNMAEGDPEAQRRVPKNPKYNTQRAERETQDSGSGNDDGGFSEEWEAQRD    SHLGP                                                                                281      290       300       310       320       330       340           350                                                                                351      360       370       380       390       400       410           420                                                                                  HRSTPESRAAVQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAIL    IGLCL                                                                                  *****************************************************************    *****                                                                                  HRSTPESRAAVQELSGSILTSEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIAXFVAIL    IGLCL                                                                                351      360       370       380       390       400       410           420                                                                                421      430       440       450       460                             C        TLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI                               ***********************************************                      C        XLLLLAIYKKGLPALPISITFGFVFXFATDYLVQPFMDQLAFHQFYI                             421      430       440       450       460                             __________________________________________________________________________

                  TABLE 4                                                         ______________________________________                                        HUMAN ARMP FUNCTIONAL DOMAINS                                                 Domains (Amino Acid Residue)                                                                     Functional Characteristic                                  ______________________________________                                         82-100 AA             Hydrophobic                                            132-154 AA             Hydrophobic                                            164-183 AA             Hydrophobic                                            195-213 AA             Hydrophobic                                            221-238 AA             Hydrophobic                                            281-299 AA             Hydrophobic                                            404-428 AA             Hydrophobic                                            431-449 AA             Hydrophobic                                            115-119 AA (YTPF)      Phosphorylation Site                                   353-356 AA (STPC)      Phosphorylation Site                                   300-385 AA             Acid Rich Domain                                                              Possible Metal Binding                                                        Domain                                                 ______________________________________                                        ANTIGENIC SITES INCLUDING AMINO ACID RESIDUES                                  27-44                                                                         46-48                                                                         50-60                                                                         66-67                                                                        107-111                                                                       120-121                                                                       125-126                                                                       155-160                                                                       185-189                                                                       214-223                                                                       220-230                                                                       240-245                                                                       267-269                                                                       273-282                                                                       300-370                                                                       400-420                                                                       ______________________________________                                    

                                      TABLE 5                                     __________________________________________________________________________             ENZYME  AMPLIFICATION                                                                           AMPLICATION                                                 (effect of                                                                            0440      0440                                               MUTATION mutation)                                                                             #1        #2          ALLELE SPECIFIC 0440                   __________________________________________________________________________    M146LEU  BsphI   910 (170-S182 F)                                                                        911 (170-S182) R                                            (destroy)                                                                             TCACAGAAGATA                                                                            CCCAACCATAAGA                                                       CCGAGACT  AGAACAG                                            MIS 163 Ary                                                                            Nla III 927 (intronic)                                                                          928                                                         (destroy)                                                                             TCTGTACTTTTT                                                                            ACTTCAGAGTAATT                                                      AAGGGTTGTG                                                                              CATCANCA                                           Ala 246  Dlc I   849*      892                                                         (create)                                                                              GACTCCAGCAGG                                                                            TGAAATCACAGCC                                                       CATATCT   AAGATGAG                                           Leu 286 Val.                                                                           Pvu II  952       951                                                         (create)                                                                              GATGAGACAAGT                                                                            CACCCATTTACAAG                                                      NCCNTGAA  TTTAGC                                                              945                                                                           TTAGTGGCTGTT                                                                  TNGTGTCC                                                     Cys 410 Tys                                                                            Allele  893       885         CCATAGCCTGTTTCGTAGC                             specific                                                                              GTGTGGCCAGGG                                                                            TGGAGACTGGAAC                                                                             890=WT                                          iligo   TAGAGAACT ACAAC       CCATAGCCTATTTCGTAGC                                                           891=MUT                                __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________    POSITION OF EXONS AND INTRON-EXON BOUNDARIES OF THE ARMP GENE                 cDNA/mRNA SEQUENCE                                                                           CORRESPONDING GENOMIC SEQUENCE                                         Transcript ID                                                                        Genomic sequence file                                          ARMP (917 ver)                                                                        CC44 ver                                                                             ID & position of exon                                                                       Comments                                         __________________________________________________________________________     1-113 bp                                                                             N/A    917-936.gen @ 731-834 bp                                                                    Alternate 5'UTR                                  N/A       1-422 bp                                                                           917-936.gen @ 1067-1475 bp                                                                  Alternate 5'UTR                                   114-195 bp                                                                            423-500 bp                                                                          932-943.gen @ 589-671 bp                                        196-335 bp                                                                            501-632 bp                                                                          932-943.gen @ 759-899 bp                                                                    12 bp Variably spliced                            337-586 bp                                                                            633-883 bp                                                                          901-912.gen @ 787-1037 bp                                       587-730 bp                                                                            884-1026 bp                                                                         910-915.gen @ 1134-1278 bp                                                                  M146L mutation                                    731-795 bp                                                                           1027-1092 bp                                                                         925-913.gen @ 413-478 bp                                                                    H163R mutation                                    796-1017 bp                                                                          1093-1314 bp                                                                         849-892.gen @ 336-558 bp                                                                    A246E mutation                                   1018-1116 bp                                                                          1315-1413 bp                                                                         951-952.gen @ 312-412 bp                                                                    L286V mutation, variable spl                     1117-1204 bp                                                                          1414-1051 bp                                                                         983-1011.gen @ 61-149 bp                                       1205-1377 bp                                                                          1502-1674 bp                                                                         874-984.gen @ 452-625 bp                                       1378-1497 bp                                                                          1674-1794 bp                                                                         885-1012.gen @ 431-550 bp                                                                   C410Y mutation                                   1498-2760 bp                                                                          1795-3060 bp                                                                         930-919.gen @ ˜10 bp-end                                                              last AA, STOP, 3'UTR                             __________________________________________________________________________

                  TABLE 7                                                         ______________________________________                                        MUTATIONS AND POLYMORPHISMS IN THE ARMP GENE                                  Nucleotide #                                                                             Amino acid #                                                       in ARMP.UPD                                                                              in ARMP.PRO  Comment                                               ______________________________________                                        A->C.sub.685                                                                             Met146Leu    Pathogenic, Unique to AD                                                      affected.                                             A->G.sub.737                                                                             His163Arg    Pathogenic, Unique to AD                                                      affected.                                             C->A.sub.986                                                                             Ala246Glu    Pathogenic, Unique to AD                                                      affected.                                             C->T.sub.1027                                                                            Ala260Val    Pathogenic, Unique to AD                                                      affected.                                             C->T.sub.1102                                                                            Ala285Val    Pathogenic, Unique to AD                                                      affected.                                             C->G.sub.1104                                                                            Leu286Val    Pathogenic, Unique to AD                                                      affected.                                             C->G.sub.1422                                                                            Leu392Val    Pathogenic, Unique to AD                                                      affected.                                             G->A.sub.1477                                                                            Cys410Tyr    Pathogenic, Unique to AD                                                      affected.                                             G->T.sub.864                                                                             Phe205Leu    Polymorphism in normals                               C->A.sub.1700                                                                            non-coding   3'UTR polymorphism                                    G->A.sub.2601                                                                            non-coding   3'UTR polymorphism                                    delC.sub.2620                                                                            non-coding   3'UTR polymorphism                                    ______________________________________                                    

                                      TABLE 8                                     __________________________________________________________________________    E5-1                                                                               1 MLTFMASDSEFFVCDERTSLMSAESPTPRSC-QEGRQGPEDGE--NTAQWRSQENEED                                                      55                                                              |  | | |          |  |   |  ||    |       |   ||| |  |         S182                                                                          -------------------MT-ELPAPLSYFQNA-QNSEDNHLSNTV--RSQ-N--D                        31                                                                         E5-1                                                                              56 G-E--EDFDRYVCS-GVP-----GRPPGL-----E------EELTLKTGAKHVIMLF                                                       92                                            |  |  ||   |               | |     ||| |             |      |||||.ve       rtline.||||||.ver       tline.|||                                       S182                                                                              51  NRERQEHNDRR--SLGHPEPLSNGRPQGNSRQVVEQDEEEDEELTLKYGAKHVIMLF                                                      86                                                                                          I                                                                             ↓               E5-1                                                                              93 VFVTLCMIVVVATIKSVRFYTEKNGQLIYTPFTEDTFSVGQRLLNSVLNTLIMISVI                                                       149                                         ||||||.vertli       ne. ||||||.vertli       ne.|| ||| |             |||||||.       vertline.||||  ||       || | | ||               ||||||               S182                                                                              87 VFVTLCMVVVVATIKSVSFYTRKDGQLIYTPFTEDTETVGQRALHSILNAAIMISVI                                                       143                                  E5-1                                                                             150 VVMTIFLVVLYKYRCYKFIHGWLIMSSLMLLFLFTYIYLGHVLKTYNVAMDYPTL-L                                                       205                                         ||||| |.vertl       ine.||||||.vertli       ne.|| || ||.vertl       ine. ||| |||            |  |||||.vertline       . ||||||                || |  |                                S182                                                                             144 VVMTILLVVLYKYRCYKVIHAWLIISSLLLLFFFSFIYLGEVFKTYNVAVDYITVAL                                                       200                                           ↑                ↑                                                L                R                                                                                           V                                                                             ↓                              E5-1                                                                             206 LTVWNFGAVGMVCIHWKGPLVLQQAYLIMISALMALVFIKYLPEWSAWVILGA-ISV                                                       261                                         |  |||| |.ver       tline.|  |||||.ve       rtline.| |||||.ve       rtline.||||||.ver       tline.||||||.vert       line.|||| ||            || | |||             S182                                                                             201 LI-WNFGVVGMISIHWKGPLRLQQAYLIMISALMALVFIKYLPEWTAWLIL-AVISV                                                       255                                                                                       ↑                                                                       E                                **********************************                                    E5-1                                                                             262 YDLVAVLCPKGFLRMLVETAQERNEPIFPALIYSSAMVWTVGMAKLDP------S--                                                       310                                         ||||||.vertli       ne.||||||.vertlin       e.||||||.vertline       .||||  ||.vertlin       e.||||| |.vertlin       e.| | ||  ||             |                                                                S182                                                                             256 YDLVAVLCFKGPLRMLVETAQERNETLFPALTYSSTMVWLVNMAFGDPEAQRRVSKN                                                       312                                           ***************************↑↑****                                                            VV                                        E5-1                                                                             311 SQGAL-------QLFY---DP----EME-EDSYDSF-GEP--SYPE----VFEPPLT                                                       345                                         |           |      |     |            | |   ||  | |           | ||    | |  |       S182                                                                             301 SKYNAESTERESQDTVAENDDGGFSE-EWEAQRDSHLG-PHRSTPESRAAVQE--LS                                                       365                                  E5-1                                                                             346 GYP--GEELEEEEERGVKLGLGDFIFYSVLVGKAAATGSFDWNTTLACFVAILIGLC                                                       400                                              ||     |||.vertli       ne.||||||.vertlin       e.||||||.vertline       .|||| ||                |||||||        |||||||.       vertline.|||                                    S182                                                                             366 SSILAGEDP---EERGVKLGLGDPIFYSVLVGKASATASDWNTTIACFVAILIGLC                                                        420                                                                       ↑                 ↑                                               V                 Y                      E5-1                                                                             401 LTLLLLAVFKKALPALPISITFGLIFYFSTDNLVRPFMDTLASRQLYI*                                                               448                                          ||||||.vertl       ine. ||||||.vertl       ine.||||||.vertli       ne.|| ||| |.vertl       ine. || ||||            |||| |||    S182                                                                             421 LTLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFRQLYI*                                                               467                                  __________________________________________________________________________

                  TABLE 9                                                         ______________________________________                                        MISSENSE MUTATIONS IN THE PRESENILIN GENES                                    ______________________________________                                        Codon location                                                                             mutation phenotype                                               ______________________________________                                        PRESENILIN I (S182)                                                            82  TM1         Val->Leu FAD, onset 55 years*                                115  TM1->TM2 loop                                                                             Tyr->His FAD, onset 37 years*                                139  TM2         Met->Thr FAD, onset 49 years*                                143  TM2         Ile->Thr FAD, onset 35 years.sup.†                    146  TM2         Met->Leu FAD, onset 45 years                                 163  TM3 interface                                                                             His->Arg FAD, onset 50 years                                 171  TM3         Leu->Pro FAD, onset 35 years                                 231  TM5         Ala->Thr FAD, onset 52 years*                                246  TM6         Ala->Glu FAD, onset 55 years                                 260  TM6         Ala->Val FAD, onset 40 years                                 264  TM6         Pro->Leu FAD, onset 45 years*                                285  TM6->TM7 loop                                                                             Ala->Val FAD, onset 50 years                                 286  TM6->TM7 loop                                                                             Leu->Val FAD, onset 50 years                                 384  TM6->TM7 loop                                                                             Gly->Ala FAD, onset 35 years.sup.†                    392  TM6->TM7 loop                                                                             Leu->Val FAD, onset 25-40 years                              410  TM7         Cys->Tyr FAD, onset 48 years                                 PRESENILIN II (E5-1)                                                          141  TM2         Asn->Ile FAD (Volga German), onset 50-65                                               years                                               239  TM5         Met->Val FAD (Florence), onset variable                      420  C-terminus  Ile->Thr FAD (Selkoe)                                        ______________________________________                                         *Campion et al., (1995).                                                      .sup.† Cruts et al., (1995).                                      

                  TABLE 10                                                        ______________________________________                                        MURINE LINES CONTAINING MUTANT OR WILD TYPE                                   HUMAN PRESENILIN TRANSGENES                                                              VECTOR TYPE (promoter:polyA)                                       GENOTYPE     haPrP:   hPDGF-β:                                                                          hβ-Actin:                                                                       hPGK:                                   (Nickname)   haPrP    SV40 pA  hGH pA PGKpA                                   ______________________________________                                        PSNL1: wild type                                                                           transgenic                                                                             transgenic                                                                             transgenic                                                                           newborn                                              mice     mice            mice                                    PSNL1: Tyr115His**             transgenic                                     (French mutation)                                                             PSNL1: Met146Leu**                                                                         transgenic                                                                             transgenic                                              (FAD4 mutation)                                                                            mice     mice                                                    PSNL1: Met146Leu(tr)  transgenic                                                                    mice                                                    PSNL1: His163Arg                                                              (603 mutation)                                                                PSNL1: Ala246Glu                      injected                                (FAD1 mutation)                                                               PSNL1: Ala260Val                      transgenic                              (JPN1 mutation)                       mice                                    PSNL1: Ala285Val                                                              (JPN2 mutation)                                                               PSNL1: Leu286Val                                                                           transgenic                                                       (Ger/FAD2 mutation)                                                                        mice                                                             PSNL1: Leu392Val**             transgenic                                     (Borras mutation)                                                             PSNL1: Cys410Tyr      transgenic                                              (MHG1/NIH2 mutation)  mice                                                    PSNL2: wild type                                                                           prepared          transgenic                                     PSNL2: Asn141Ile                                                                           injected          transgenic                                     (Volga mutation)                                                              PSNL2: Met239Val                                                                           prepared          transgenic                                     (FLO1O mutation)                                                              ______________________________________                                         **Mutations associated with onset ≦45 years of age.               

                  TABLE 11                                                        ______________________________________                                        C. elegans transgenes                                                                    Vector                                                             GENOTYPE     pPD49.3 hsp 16-41                                                                          pPD49.78 hsp 16-2                                   ______________________________________                                        PSNL1: wild type                                                                           transgenic   injected                                                         C. elegans                                                       PSNL1: Leu392Val                                                                           transgenic   injected                                                         C. elegans                                                       PSNL1: Met146Leu                                                                           prepared     prepared                                            + Leu392Val; cis double                                                       mutation                                                                      PSNL2: wild type                                                                           prepared     prepared                                            PSNL2: ASN141Ile                                                                           prepared     prepared                                            ______________________________________                                    

                                      TABLE 12                                    __________________________________________________________________________    Platelet derived growth factor promoter (PDGF) (vector  pZEOsV)               a) S182                                                                       0 #STR7##                                                                     Construct released by HindIII/BamHI digestion                                 b) S182 Truncated (S182t)                                                     1 #STR8##                                                                     Construct released by ScaI/BamHI digestion                                    c) E5-1                                                                       2 #STR9##                                                                     Construct released by ScaI/BamHI digestion                                    Legend: S = SpeI; H = HindIII; K = KpnI; E = EcoRI; B = BstXI; N = NotI;      X = XhoI                                                                      β actin promoter (vector pGem11 Zf')                                     a) S182                                                                       3 #STR10##                                                                    b) S182 Truncated (S182t)                                                     4 #STR11##                                                                    c) E5-1                                                                       5 #STR12##                                                                    Legend: ut = 5' untranslate; Prom = promoter; E = EcoRI; N = NotI; S =        SalI; X = XhoI                                                                B = BamHI; K = KpnI                                                           Constructs released by SfiI digestion                                         Phosphoglycerate promotor construct (PGK) (vector pPOP)                       a) S182                                                                       6 #STR13##                                                                    Construct released by PvuII/HindIII digestion                                 b) S182 Truncated (S182t)                                                     7 #STR14##                                                                    Construct released by PvuII/HindIII digestion                                 c) E5-1                                                                       8 #STR15##                                                                    Construct released by PvuII digestion                                         Legend: P = PvuII; E = EcoRI; K = KpnI; B = BstXI; N = NotI; X ==0 XhoI;      H = HindIII                                                                   __________________________________________________________________________

                                      TABLE 13                                    __________________________________________________________________________    Gene name  U of T clone                                                                        EST                                                          (official) ID    in database                                                                         Putative gene function                                 __________________________________________________________________________    RabII      ps1ly2h-9                                                                           X56740                                                                              Protein/vesicle traffic in ER/Golgi.                                    X53143                                                                              NB possible relationship to processing                                        of membrane proteins such as βAPP                                        and Notch with resultant                                                      overproduction of toxic Aβ peptides                                      (esp. neurotoxic Aβ.sub.1-42(43) isoforms)                               (Scheuner, et al, 1995).                               retinoid X receptor-B;                                                                   ps1ly2h23b                                                                          m8420 Gene involved in inter-cellular                        nuclear receptor co-                                                                           x63522                                                                              signalling - NB possible relationship                  regulator; MHCclass I                                                                          m181766                                                                             to intercellular signalling function                   regulatory element     mediated by C. elegans sel12                                                  (homologue of mammalian presenilins)                                          and C. elegans Notch/lin-12                                                   (transcription activator).                             unknown gene                                                                             ps1ly2h-6                                                                           F08730                                                                              Weak homology to Cyclic AMP                                       ps1ly2y10b                                                                          T18858                                                                              response element binding protein                                  ps1ly2h17h2                                                                         H17245                                                                              (CREB) involved in transcriptional                                ps1ly2h24                                                                           T06654                                                                              responses to extracellular signals as                                   T77214                                                                              a second messenger pathway. Strong                                      h24294                                                                              homology to p120 (NOL) protein also                               ps1ly2h25                                                                           M62015                                                                              involved in transcription and cell cycle                                T87427                                                                              events. Note that these transcriptional                                 G04019                                                                              event regulatory effects are similar to                                       those postulated for Notch/lin-12                                             mediated effects on intercellular                                             signalling. Activation of genes (eg                                           βAPP) causing over-expression of                                         βAPP mRNA has been shown in                                              subjects with mutations in the                                                presenilins (Querforth et al, 1995).                                          Modulation of this abberrant                                                  transcriptional activation could be used                                      as a therapeutic target to correct                                            abnormalities in the expression of                                            genes (including βAPP and other                                          genes) and thereby prevent/improve                                            the symptoms of AD.                                    unknown gene                                                                             psl1y2h-6                                                                           F08730                                                                              Weak homology to plakophilin                           (cont'd)   ps1ly2y10b                                                                          T18858                                                                              a protein involved in stabilization                               ps1ly2h17h2                                                                         H17245                                                                              of the cytoskeletal fibrillar proteins                            PS1LY2H24                                                                           ETC   Note that more than one member of                                 ps1ly2h24                                                                           (cont'd)                                                                            member of the is gene family was                                  (cont'd)    isolated, suggesting a family of                                              genes interacting differentially with                                         different presenilins. Note that                                              defects in the cytoskeleton (ie                                               paired helical filaments and                                                  neurofibrillary tangles) are a major                                          neuropathologic hallmark of AD.                        antisecretory factor                                                                     ps1ly2h-29                                                                          U24707                                                                              Secretion of fluid in gut, unknown in                             ps1ly2h-31  brain.                                                 unknown gene                                                                             ps1ly2h-35                                                                          R12984                                                                              homology down to yeast, function =                                            unknown.                                               cytoplasmic chaperonin                                                                   ph1ly2h-27                                                                          U17104                                                                              Chaperonin containing TCP-1                                             X74801                                                       unknown gene                                                                             ps1ly2h-41                                                                          T64843                                                                              unknown ESTs. Note: this gene                                           F12194                                                                              product reacts strongly with                                                  both PS-1 and PS-2 which argues                                               for a real effect related to the                                              shared biochemical effects of                                                 PS-1 and PS-2 causing AD.                              unknown gene                                                                             ps1y12h-171                                                                         D55326                                                                              expressed repeat sequence                              __________________________________________________________________________

                                      TABLE 14                                    __________________________________________________________________________    File1: drops.concensus (1-541) vs File2: PS-1 (s182) (1-468)                  Matching Percentage:53%   = S182/E5-1 mutations* = alternate                  splice: g384-<A384 and in frame fusion to E399                                __________________________________________________________________________      1 MAAVNLQASCSSGL-A--SEDDA--N-VGSQIGAAERLERPPRRQQQRNN                                                              50                                          |    | |  |    |                 |||    | | |.ver        tline.    || |   ||            1 MTE--LPAPLSYFQNAQMSEDNHLSNTVRSQNDNRERQEHNDRR------                                                              50                                       51 YGSSNQDQPDAAILAVPNVVMREPCGS--RPSRLTGGGGGSGGPPTN-EM                                                             100                                            |          |  |     ||          |  ||    |    |                 |                                                                 51                                                                           S----------LGHP-----EPL-SNGRPQ---GN---SRQVVEQDEE                                  100                                                                       101 E-EEQGLKYGAQHVIKLFVPVSLCMLVVVATINSISFYNST--DVYLLYT                                                             150                                          | ||  |||.vertli        ne.| ||| ||.vert        line.|| ||| |.ve        rtline.|||| | |.        vertline.|  |  | ||          101 EDEELTLKYGAKHVIMLFVPVTLCMVVVVATIKSVSFY--TRKDGQIYT                                                              150                                      151 PFHEQSPEPSVKFW-SALANSLILMSVVVVMTFLLIVLYKKRCYRI                                                                 200                                          || |           | |               |  |  || ||.vert        line.|||| ||.ver        tline.|||||                  151 PFTEDTETVGQRALHSIL-NAAIMISVIVVMTILLVVLYKYRCYKV                                                                 200                                      201 IHGWLILSSFMLLFIFTYLYLEELLRAYNIPMDYPT-ALLIMWNFGVVGM                                                             250                                          || ||| |.vertlin        e.  ||| |   ||          |    ||   || |          |||| ||.vertline        .|||||                       201 IHAWLIISSLLLLFFFSFIYLGEVFKTYNVAVDYITVALLI-WNFGVVGM                                                             250                                      251 MSIHWQGPLRLQQGYLIFVAALMALVFIKYLPEWTAWAVLAAISIWDLIA                                                             300                                           |||| ||.vertlin        e.|||| ||.vertli        ne.   ||||||.ver        tline.||||||.ver        tline.|||  || |.        vertline.  || |                                251 ISIHWKGPLRLOOAYLIMISALMALVFIKYLPEWTAWLILAVISVYDLVA                                                             300                                                                                        ***                         301 VLSPRGPLXILVETAQERNEQIFPALIYSSTVVYALVNTVT--PQQSQAT                                                             350                                          || | |||.vertlin        e. ||||||.vertli        ne.|||  |||.vert        line.||||| |            |||     |   |                301 VLCPKGPLRMLVETAQERNETLFPALIYSSTMVW-LVNMAEGDPEA-QRR                                                             350                                          ************************  ****                                            351 ASSSPSSSN--STTTTRATQNSLASPEAAAASGQRTGNSHPRQNQRDDGS                                                             400                                           |   |  |  ||   .vertline        .  |   |  |     |   |            |     |||  |                 351 VSKN-SKYNAESTE--RESQDTVA--ENDD--G---GFSEEWEAQRD--S                                                             400                                               ***** **********                                                     401 VLATEGMPLV-TFKSNLRGNAEAAGFTQEWSANLSERVARRQIEVQSTQS                                                             450                                           |   | |   |  |                  |  | |    ||    .vertline        .|           |  |                              401 HL---G-PHRSTPES--R--A-AV---QE----LS-----------S--S                                                             450                                      451 GNAQRSNEYRTVTAPDQNHPDGQEERGIKLGLGDFIFYSVLVGKAS---S                                                             500                                            |    |       |   |   |.        vertline.|| ||||        |||||||        |||||||           |                                                             451 ILAG---E-------D---P---EERGVKLGLGDFIFYSVLVGKASATAS                                                             500                                      501 YGDWTTTIACFVAILIGLCLTLLLLAIWRKALPALPISITFGLIFCFATS                                                             550                                           ||| |||.vertlin        e.||||||.vertlin        e.||||||.vertlin        e.||||  ||.vertl        ine.||||||.vertl        ine.|||| | |.ver        tline.|                                                          501                                                                           GDWNTTIACFVAILIGLCLTLLLLAIFKKALPALPISITFGLVFYFATD                                 550                                                                       551 AVVKPRMED-LSAK-QVF-I*..............................                                                            600                                            | ||| | |             |  | | |                              551 YLVQPFM-DQL-AFHQ-FYL*..............................                                                            600                                      __________________________________________________________________________

    __________________________________________________________________________    #             SEQUENCE LISTING                                                - (1) GENERAL INFORMATION:                                                    -    (iii) NUMBER OF SEQUENCES: 183                                           - (2) INFORMATION FOR SEQ ID NO:1:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 2791 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                 - TGGGACAGGC AGCTCCGGGG TCCGCGGTTT CACATCGGAA ACAAAACAGC GG - #CTGGTCTG         60                                                                          - GAAGGAACCT GAGCTACGAG CCGCGGCGGC AGCGGGGCGG CGGGGNAAGC GT - #ATACCTAA        120                                                                          - TCTGGGAGCC TGCAAGTGAC AACAGCCTTT GCGGTCCTTA GACAGCTTGG CC - #TGGAGGAG        180                                                                          - AACACATGAA AGAAAGAACC TCAAGAGGCT TTGTTTTCTG TGAAACAGTA TT - #TCTATACA        240                                                                          - GTTGCTCCAA TGACAGAGTT ACCTGCACCG TTGTCCTACT TCCAGAATGC AC - #AGATGTCT        300                                                                          - GAGGACAACC ACCTGAGCAA TACTGTACGT AGCCAGAATG ACAATAGAGA AC - #GGCAGGAG        360                                                                          - CACAACGACA GACGGAGCCT TGGCCACCCT GAGCCATTAT CTAATGGACG AC - #CCCAGGGT        420                                                                          - AACTCCCGGC AGGTGGTGGA GCAAGATGAG GAAGAAGATG AGGAGCTGAC AT - #TGAAATAT        480                                                                          - GGCGCCAAGC ATGTGATCAT GCTCTTTGTC CCTGTGACTC TCTGCATGGT GG - #TGGTCGTG        540                                                                          - GCTACCATTA AGTCAGTCAG CTTTTATACC CGGAAGGATG GGCAGCTAAT CT - #ATACCCCA        600                                                                          - TTCACAGAAG ATACCGAGAC TGTGGGCCAG AGAGCCCTGC ACTCAATTCT GA - #ATGCTGCC        660                                                                          - ATCATGATCA GTGTCATTGT TGTCATGACT ATCCTCCTGG TGGTTCTGTA TA - #AATACAGG        720                                                                          - TGCTATAAGG TCATCCATGC CTGGCTTATT ATATCATCTC TATTGTTGCT GT - #TCTTTTTT        780                                                                          - TCATTCATTT ACTTGGGGGA AGTGTTTAAA ACCTATAACG TTGCTGTGGA CT - #ACATTACT        840                                                                          - GTTGCACTCC TGATCTGGAA TTTGGGTGTG GTGGGAATGA TTTCCATTCA CT - #GGAAAGGT        900                                                                          - CCACTTCGAC TCCAGCAGGC ATATCTCATT ATGATTAGTG CCCTCATGGC CC - #TGGTGTTT        960                                                                          - ATCAAGTACC TCCCTGAATG GACTGCGTGG CTCATCTTGG CTGTGATTTC AG - #TATATGAT       1020                                                                          - TTAGTGGCTG TTTTGTGTCC GAAAGGTCCA CTTCGTATGC TGGTTGAAAC AG - #CTCAGGAG       1080                                                                          - AGAAATGAAA CGCTTTTTCC AGCTCTCATT TACTCCTCAA CAATGGTGTG GT - #TGGTGAAT       1140                                                                          - ATGGCAGAAG GAGACCCGGA AGCTCAAAGG AGAGTATCCA AAAATTCCAA GT - #ATAATGCA       1200                                                                          - GAAAGCACAG AAAGGGAGTC ACAAGACACT GTTGCAGAGA ATGATGATGG CG - #GGTTCAGT       1260                                                                          - GAGGAATGGG AAGCCCAGAG GGACAGTCAT CTAGGGCCTC ATCGCTCTAC AC - #CTGAGTCA       1320                                                                          - CGAGCTGCTG TCCAGGAACT TTCCAGCAGT ATCCTCGCTG GTGAAGACCC AG - #AGGAAAGG       1380                                                                          - GGAGTAAAAC TTGGATTGGG AGATTTCATT TTCTACAGTG TTCTGGTTGG TA - #AAGCCTCA       1440                                                                          - GCAACAGCCA GTGGAGACTG GAACACAACC ATAGCCTGTT TCGTAGCCAT AT - #TAATTGGT       1500                                                                          - TTGTGCCTTA CATTATTACT CCTTGCCATT TTCAAGAAAG CATTGCCAGC TC - #TTCCAATC       1560                                                                          - TCCATCACCT TTGGGCTTGT TTTCTACTTT GCCACAGATT ATCTTGTACA GC - #CTTTTATG       1620                                                                          - GACCAATTAG CATTCCATCA ATTTTATATC TAGCATATTT GCGGTTAGAA TC - #CCATGGAT       1680                                                                          - GTTTCTTCTT TGACTATAAC CAAATCTGGG GAGGACAAAG GTGATTTTCC TG - #TGTCCACA       1740                                                                          - TCTAACAAAG TCAAGATTCC CGGCTGGACT TTTGCAGCTT CCTTCCAAGT CT - #TCCTGACC       1800                                                                          - ACCTTGCACT ATTGGACTTT GGAAGGAGGT GCCTATAGAA AACGATTTTG AA - #CATACTTC       1860                                                                          - ATCGCAGTGG ACTGTGTCCT CGGTGCAGAA ACTACCAGAT TTGAGGGACG AG - #GTCAAGGA       1920                                                                          - GATATGATAG GCCCGGAAGT TGCTGTGCCC CATCAGCAGC TTGACGCGTG GT - #CACAGGAC       1980                                                                          - GATTTCACTG ACACTGCGAA CTCTCAGGAC TACCGGTTAC CAAGAGGTTA GG - #TGAAGTGG       2040                                                                          - TTTAAACCAA ACGGAACTCT TCATCTTAAA CTACACGTTG AAAATCAACC CA - #ATAATTCT       2100                                                                          - GTATTAACTG AATTCTGAAC TTTTCAGGAG GTACTGTGAG GAAGAGCAGG CA - #CCAGCAGC       2160                                                                          - AGAATGGGGA ATGGAGAGGT GGGCAGGGGT TCCAGCTTCC CTTTGATTTT TT - #GCTGCAGA       2220                                                                          - CTCATCCTTT TTAAATGAGA CTTGTTTTCC CCTCTCTTTG AGTCAAGTCA AA - #TATGTAGA       2280                                                                          - TGCCTTTGGC AATTCTTCTT CTCAAGCACT GACACTCATT ACCGTCTGTG AT - #TGCCATTT       2340                                                                          - CTTCCCAAGG CCAGTCTGAA CCTGAGGTTG CTTTATCCTA AAAGTTTTAA CC - #TCAGGTTC       2400                                                                          - CAAATTCAGT AAATTTTGGA AACAGTACAG CTATTTCTCA TCAATTCTCT AT - #CATGTTGA       2460                                                                          - AGTCAAATTT GGATTTTCCA CCAAATTCTG AATTTGTAGA CATACTTGTA CG - #CTCACTTG       2520                                                                          - CCCCAGATGC CTCCTCTGTC CTCATTCTTC TCTCCCACAC AAGCAGTCTT TT - #TCTACAGC       2580                                                                          - CAGTAAGGCA GCTCTGTCGT GGTAGCAGAT GGTCCCACTT ATTCTAGGGT CT - #TACTCTTT       2640                                                                          - GTATGATGAA AAGAATGTGT TATGAATCGG TGCTGTCAGC CCTGCTGTCA GA - #CCTTCTTC       2700                                                                          - CACAGCAAAT GAGATGTATG CCCAAAGCGG TAGAATTAAA GAAGAGTAAA AT - #GGCTGTTG       2760                                                                          #        2791      AAAA AAAAAAAAAA A                                          - (2) INFORMATION FOR SEQ ID NO:2:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 467 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                 -      Met Thr Glu Leu Pro Ala Pro Leu - # Ser Tyr Phe Gln Asn Ala Gln        Met                                                                           #   15                                                                        -      Ser Glu Asp Asn His Leu Ser Asn - # Thr Val Arg Ser Gln Asn Asp        Asn                                                                           #                 30                                                          -      Arg Glu Arg Gln Glu His Asn Asp - # Arg Arg Ser Leu Gly His Pro        Glu                                                                           #             45                                                              -      Pro Leu Ser Asn Gly Arg Pro Gln - # Gly Asn Ser Arg Gln Val Val        Glu                                                                           #         60                                                                  -      Gln Asp Glu Glu Glu Asp Glu Glu - # Leu Thr Leu Lys Tyr Gly Ala        Lys                                                                           #     80                                                                      -      His Val Ile Met Leu Phe Val Pro - # Val Thr Leu Cys Met Val Val        Val                                                                           #   95                                                                        -      Val Ala Thr Ile Lys Ser Val Ser - # Phe Tyr Thr Arg Lys Asp Gly        Gln                                                                           #                110                                                          -      Leu Ile Tyr Thr Pro Phe Thr Glu - # Asp Thr Glu Thr Val Gly Gln        Arg                                                                           #            125                                                              -      Ala Leu His Ser Ile Leu Asn Ala - # Ala Ile Met Ile Ser Val Ile        Val                                                                           #        140                                                                  -      Val Met Thr Ile Leu Leu Val Val - # Leu Tyr Lys Tyr Arg Cys Tyr        Lys                                                                           #    160                                                                      -      Val Ile His Ala Trp Leu Ile Ile - # Ser Ser Leu Leu Leu Leu Phe        Phe                                                                           #   175                                                                       -      Phe Ser Phe Ile Tyr Leu Gly Glu - # Val Phe Lys Thr Tyr Asn Val        Ala                                                                           #                190                                                          -      Val Asp Tyr Ile Thr Val Ala Leu - # Leu Ile Trp Asn Leu Gly Val        Val                                                                           #            205                                                              -      Gly Met Ile Ser Ile His Trp Lys - # Gly Pro Leu Arg Leu Gln Gln        Ala                                                                           #        220                                                                  -      Tyr Leu Ile Met Ile Ser Ala Leu - # Met Ala Leu Val Phe Ile Lys        Tyr                                                                           #    240                                                                      -      Leu Pro Glu Trp Thr Ala Trp Leu - # Ile Leu Ala Val Ile Ser Val        Tyr                                                                           #   255                                                                       -      Asp Leu Val Ala Val Leu Cys Pro - # Lys Gly Pro Leu Arg Met Leu        Val                                                                           #                270                                                          -      Glu Thr Ala Gln Glu Arg Asn Glu - # Thr Leu Phe Pro Ala Leu Ile        Tyr                                                                           #            285                                                              -      Ser Ser Thr Met Val Trp Leu Val - # Asn Met Ala Glu Gly Asp Pro        Glu                                                                           #        300                                                                  -      Ala Gln Arg Arg Val Ser Lys Asn - # Ser Lys Tyr Asn Ala Glu Ser        Thr                                                                           #    320                                                                      -      Glu Arg Glu Ser Gln Asp Thr Val - # Ala Glu Asn Asp Asp Gly Gly        Phe                                                                           #   335                                                                       -      Ser Glu Glu Trp Glu Ala Gln Arg - # Asp Ser His Leu Gly Pro His        Arg                                                                           #                350                                                          -      Ser Thr Pro Glu Ser Arg Ala Ala - # Val Gln Glu Leu Ser Ser Ser        Ile                                                                           #            365                                                              -      Leu Ala Gly Glu Asp Pro Glu Glu - # Arg Gly Val Lys Leu Gly Leu        Gly                                                                           #        380                                                                  -      Asp Phe Ile Phe Tyr Ser Val Leu - # Val Gly Lys Ala Ser Ala Thr        Ala                                                                           #    400                                                                      -      Ser Gly Asp Trp Asn Thr Thr Ile - # Ala Cys Phe Val Ala Ile Leu        Ile                                                                           #   415                                                                       -      Gly Leu Cys Leu Thr Leu Leu Leu - # Leu Ala Ile Phe Lys Lys Ala        Leu                                                                           #                430                                                          -      Pro Ala Leu Pro Ile Ser Ile Thr - # Phe Gly Leu Val Phe Tyr Phe        Ala                                                                           #            445                                                              -      Thr Asp Tyr Leu Val Gln Pro Phe - # Met Asp Gln Leu Ala Phe His        Gln                                                                           #        460                                                                  -      Phe Tyr Ile                                                                 465                                                                      - (2) INFORMATION FOR SEQ ID NO:3:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1929 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                 - ACCANACANC GGCAGCTGAG GCGGAAACCT AGGCTGCGAG CCGGCCGCCC GG - #GCGCGGAG         60                                                                          - AGAGAAGGAA CCAACACAAG ACAGCAGCCC TTCGAGGTCT TTAGGCAGCT TG - #GAGGAGAA        120                                                                          - CACATGAGAG AAAGAATCCC AAGAGGTTTT GTTTTCTTTG AGAAGGTATT TC - #TGTCCAGC        180                                                                          - TGCTCCAATG ACAGAGATAC CTGCACCTTT GTCCTACTTC CAGAATGCCC AG - #ATGTCTGA        240                                                                          - GGACAGCCAC TCCAGCAGCG CCATCCGGAG CCAGAATGAC AGCCAAGAAC GG - #CAGCAGCA        300                                                                          - GCATGACAGG CAGAGACTTG ACAACCCTGA GCCAATATCT AATGGGCGGC CC - #CAGAGTAA        360                                                                          - CTCAAGACAG GTGGTGGAAC AAGATGAGGA GGAAGACGAA GAGCTGACAT TG - #AAATATGG        420                                                                          - AGCCAAGCAT GTCATCATGC TCTTTGTCCC CGTGACCCTC TGCATGGTCG TC - #GTCGTGGC        480                                                                          - CACCATCAAA TCAGTCAGCT TCTATACCCG GAAGGACGGT CAGCTAATCT AC - #ACCCCATT        540                                                                          - CACAGAAGAC ACTGAGACTG TAGGCCAAAG AGCCCTGCAC TCGATCCTGA AT - #GCGGCCAT        600                                                                          - CATGATCAGT GTCATTGTCA TTATGACCAT CCTCCTGGTG GTCCTGTATA AA - #TACAGGTG        660                                                                          - CTACAAGGTC ATCCACGCCT GGCTTATTAT TTCATCTCTG TTGTTGCTGT TC - #TTTTTTTC        720                                                                          - GTTCATTTAC TTAGGGGAAG TATTTAAGAC CTACAATGTC KCCGTGGACT AC - #GTTACAGT        780                                                                          - AGCACTCCTA ATCTGGAATT GGGGTGTGGT CGGGATGATT GCCATCCACT GG - #AAAGGCCC        840                                                                          - CCTTCGACTG CAGCAGGCGT ATCTCATTAT GATCAGTGCC CTCATGGCCC TG - #GTATTTAT        900                                                                          - CAAGTACCTC CCCGAATGGA CCGCATGGCT CATCTTGGCT GTGATTTCAG TA - #TATGATTT        960                                                                          - GGTGGCTGTT TTATGTCCCA AAGGCCCACT TCGTATGCTG GTTGAAACAG CT - #CAGGAAAG       1020                                                                          - AAATGAGACT CTCTTTCCAG CTCTTATCTA TTCCTCAACA ATGGTGTGGT TG - #GTGAATAT       1080                                                                          - GGCTGAAGGA GACCCAGAAG CCCAAAGGAG GGTACCCAAG AACCCCAAGT AT - #AACACACA       1140                                                                          - AAGAGCGGAG AGAGAGACAC AGGACAGTGG TTCTGGGAAC GATGATGGTG GC - #TTCAGTGA       1200                                                                          - GGAGTGGGAG GCCCAAAGAG ACAGTCACCT GGGGCCTCAT CGCTCCACTC CC - #GAGTCAAG       1260                                                                          - AGCTGCTGTC CAGGAACTTT CTGGGAGCAT TCTAACGAGT GAAGACCCGG AG - #GAAAGAGG       1320                                                                          - AGTAAAACTT GGACTGGGAG ATTTCATTTT CTACAGTGTT CTGGTTGGTA AG - #GCCTCAGC       1380                                                                          - AACCGCCAGT GGAGACTGGA ACACAACCAT AGCCTGCTTK GTAGCCATAC TG - #ATCGGCCT       1440                                                                          - GTGCCTTANA TTACTCCTGC TCGCCATTTA CAAGAAAGGG TNGCCAGCCC NC - #CCCATCTC       1500                                                                          - CATCACCTTC GGGTTCGTGT TCTNCTTCGC CACGGATTAC CTTGTGCAGC CC - #TTCATGGA       1560                                                                          - CCAACTTGCA TTCCATCAGT TTTATATCTA GCCTTTCTGC AGTTAGAACA TG - #GATGTTTC       1620                                                                          - TTCTTTGATT ATCAAAAACA CAAAAACAGA GAGCAAGCCC GAGGAGGAGA CT - #GGTGACTT       1680                                                                          - TCCTGTGTCC TCAGCTAACA AAGGCAGGAC TCCAGCTGGA CTTCTGCAGC TT - #CCTTCCGA       1740                                                                          - GTCTCCCTAG CCACCCGCAC TACTGGACTG TGGAAGGAAG CGTCTACAGA GG - #AACGGTTT       1800                                                                          - CCAACATCCA TCGCTGCAGC AGACGGTGTC CCTCAGTGAC TTGAGAGACA AG - #GACAAGGA       1860                                                                          - AATGTGCTGG GCCAAGGAGC TGCCGTGCTC TGCTAGCTTT GGMCCGTGGG CA - #TGGAGATT       1920                                                                          #       1929                                                                  - (2) INFORMATION FOR SEQ ID NO:4:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 467 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                 -      Met Thr Glu Ile Pro Ala Pro Leu - # Ser Tyr Phe Gln Asn Ala Gln        Met                                                                           #   15                                                                        -      Ser Glu Asp Ser His Ser Ser Ser - # Ala Ile Arg Ser Gln Asn Asp        Ser                                                                           #                 30                                                          -      Gln Glu Arg Gln Gln Gln His Asp - # Arg Gln Arg Leu Asp Asn Pro        Glu                                                                           #             45                                                              -      Pro Ile Ser Asn Gly Arg Pro Gln - # Ser Asn Ser Arg Gln Val Val        Glu                                                                           #         60                                                                  -      Gln Asp Glu Glu Glu Asp Glu Glu - # Leu Thr Leu Lys Tyr Gly Ala        Lys                                                                           #     80                                                                      -      His Val Ile Met Leu Phe Val Pro - # Val Thr Leu Cys Met Val Val        Val                                                                           #   95                                                                        -      Val Ala Thr Ile Lys Ser Val Ser - # Phe Tyr Thr Arg Lys Asp Gly        Gln                                                                           #                110                                                          -      Leu Ile Tyr Thr Pro Phe Thr Glu - # Asp Thr Glu Thr Val Gly Gln        Arg                                                                           #            125                                                              -      Ala Leu His Ser Ile Leu Asn Ala - # Ala Ile Met Ile Ser Val Ile        Val                                                                           #        140                                                                  -      Ile Met Thr Ile Leu Leu Val Val - # Leu Tyr Lys Tyr Arg Cys Tyr        Lys                                                                           #    160                                                                      -      Val Ile His Ala Trp Leu Ile Ile - # Ser Ser Leu Leu Leu Leu Phe        Phe                                                                           #   175                                                                       -      Phe Ser Phe Ile Tyr Leu Gly Glu - # Val Phe Lys Thr Tyr Asn Val        Xaa                                                                           #                190                                                          -      Val Asp Tyr Val Thr Val Ala Leu - # Leu Ile Trp Asn Trp Gly Val        Val                                                                           #            205                                                              -      Gly Met Ile Ala Ile His Trp Lys - # Gly Pro Leu Arg Leu Gln Gln        Ala                                                                           #        220                                                                  -      Tyr Leu Ile Met Ile Ser Ala Leu - # Met Ala Leu Val Phe Ile Lys        Tyr                                                                           #    240                                                                      -      Leu Pro Glu Trp Thr Ala Trp Leu - # Ile Leu Ala Val Ile Ser Val        Tyr                                                                           #   255                                                                       -      Asp Leu Val Ala Val Leu Cys Pro - # Lys Gly Pro Leu Arg Met Leu        Val                                                                           #                270                                                          -      Glu Thr Ala Gln Glu Arg Asn Glu - # Thr Leu Phe Pro Ala Leu Ile        Tyr                                                                           #            285                                                              -      Ser Ser Thr Met Val Trp Leu Val - # Asn Met Ala Glu Gly Asp Pro        Glu                                                                           #        300                                                                  -      Ala Gln Arg Arg Val Pro Lys Asn - # Pro Lys Tyr Asn Thr Gln Arg        Ala                                                                           #    320                                                                      -      Glu Arg Glu Thr Gln Asp Ser Gly - # Ser Gly Asn Asp Asp Gly Gly        Phe                                                                           #   335                                                                       -      Ser Glu Glu Trp Glu Ala Gln Arg - # Asp Ser His Leu Gly Pro His        Arg                                                                           #                350                                                          -      Ser Thr Pro Glu Ser Arg Ala Ala - # Val Gln Glu Leu Ser Gly Ser        Ile                                                                           #            365                                                              -      Leu Thr Ser Glu Asp Pro Glu Glu - # Arg Gly Val Lys Leu Gly Leu        Gly                                                                           #        380                                                                  -      Asp Phe Ile Phe Tyr Ser Val Leu - # Val Gly Lys Ala Ser Ala Thr        Ala                                                                           #    400                                                                      -      Ser Gly Asp Trp Asn Thr Thr Ile - # Ala Cys Xaa Val Ala Ile Leu        Ile                                                                           #   415                                                                       -      Gly Leu Cys Leu Xaa Leu Leu Leu - # Leu Ala Ile Tyr Lys Lys Gly        Xaa                                                                           #                430                                                          -      Pro Ala Xaa Pro Ile Ser Ile Thr - # Phe Gly Phe Val Phe Xaa Phe        Ala                                                                           #            445                                                              -      Thr Asp Tyr Leu Val Gln Pro Phe - # Met Asp Gln Leu Ala Phe His        Gln                                                                           #        460                                                                  -      Phe Tyr Ile                                                                 465                                                                      - (2) INFORMATION FOR SEQ ID NO:5:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 3087 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                 - GAATTCGGCA CGAGGGAAAT GCTGTTTGCT CGAAGACGTC TCAGGGCGCA GG - #TGCCTTGG         60                                                                          - GCCGGGATTA GTAGCCGTCT GAACTGGAGT GGAGTAGGAG AAAGAGGAAG CG - #TCTTGGGC        120                                                                          - TGGGTCTGCT TGAGCAACTG GTGAAACTCC GCGCCTCACG CCCCGGGTGT GT - #CCTTGTCC        180                                                                          - AGGGGCGACG AGCATTCTGG GCGAAGTCCG CACSCCTCTT GTTCGAGGCG GA - #AGACGGGG        240                                                                          - TCTGATSCTT TCTCCTTGGT CGGGMCTGTC TCGAGGCATG CATGTCCAGT GA - #CTCTTGTG        300                                                                          - TTTGCTGCTG CTTCCCTCTC AGATTCTTCT CACCGTTGTG GTCAGCTCTG CT - #TTAGGCAN        360                                                                          - TATTAATCCA TAGTGGAGGC TGGGATGGGT GAGAGAATTG AGGTGACTTT TC - #CATAATTC        420                                                                          - AGACCTAATC TGGGAGCCTG CAAGTGACAA CAGCCTTTGC GGTCCTTAGA CA - #GCTTGGCC        480                                                                          - TGGAGGAGAA CACATGAAAG AAAGAACCTC AAGAGGCTTT GTTTTCTGTG AA - #ACAGTATT        540                                                                          - TCTATACAGT TGCTCCAATG ACAGAGTTAC CTGCACCGTT GTCCTACTTC CA - #GAATGCAC        600                                                                          - AGATGTCTGA GGACAACCAC CTGAGCAATA CTAATGACAA TAGAGAACGG CA - #GGAGCACA        660                                                                          - ACGACAGACG GAGCCTTGGC CACCCTGAGC CATTATCTAA TGGACGACCC CA - #GGGTAACT        720                                                                          - CCCGGCAGGT GGTGGAGCAA GATGAGGAAG AAGATGAGGA GCTGACATTG AA - #ATATGGCG        780                                                                          - CCAAGCATGT GATCATGCTC TTTGTCCCTG TGACTCTCTG CATGGTGGTG GT - #CGTGGCTA        840                                                                          - CCATTAAGTC AGTCAGCTTT TATACCCGGA AGGATGGGCA GCTAATCTAT AC - #CCCATTCA        900                                                                          - CAGAAGATAC CGAGACTGTG GGCCAGAGAG CCCTGCACTC AATTCTGAAT GC - #TGCCATCA        960                                                                          - TGATCAGTGT CATTGTTGTC ATGACTATCC TCCTGGTGGT TCTGTATAAA TA - #CAGGTGCT       1020                                                                          - ATAAGGTCAT CCATGCCTGG CTTATTATAT CATCTCTATT GTTGCTGTTC TT - #TTTTTCAT       1080                                                                          - TCATTTACTT GGGGGAAGTG TTTAAAACCT ATAACGTTGC TGTGGACTAC AT - #TACTGTTG       1140                                                                          - CACTCCTGAT CTGGAATTTG GGTGTGGTGG GAATGATTTC CATTCACTGG AA - #AGGTCCAC       1200                                                                          - TTCGACTCCA GCAGGCATAT CTCATTATGA TTAGTGCCCT CATGGCCCTG GT - #GTTTATCA       1260                                                                          - AGTACCTCCC TGAATGGACT GCGTGGCTCA TCTTGGCTGT GATTTCAGTA TA - #TGATTTAG       1320                                                                          - TGGCTGTTTT GTGTCCGAAA GGTCCACTTC GTATGCTGGT TGAAACAGCT CA - #GGAGAGAA       1380                                                                          - ATGAAACGCT TTTTCCAGCT CTCATTTACT CCTCAACAAT GGTGTGGTTG GT - #GAATATGG       1440                                                                          - CAGAAGGAGA CCCGGAAGCT CAAAGGAGAG TATCCAAAAA TTCCAAGTAT AA - #TGCAGAAA       1500                                                                          - GCACAGAAAG GGAGTCACAA GACACTGTTG CAGAGAATGA TGATGGCGGG TT - #CAGTGAGG       1560                                                                          - AATGGGAAGC CCAGAGGGAC AGTCATCTAG GGCCTCATCG CTCTACACCT GA - #GTCACGAG       1620                                                                          - CTGCTGTCCA GGAACTTTCC AGCAGTATCC TCGCTGGTGA AGACCCAGAG GA - #AAGGGGAG       1680                                                                          - TAAAACTTGG ATTGGGAGAT TTCATTTTCT ACAGTGTTCT GGTTGGTAAA GC - #CTCAGCAA       1740                                                                          - CAGCCAGTGG AGACTGGAAC ACAACCATAG CCTGTTTCGT AGCCATATTA AT - #TGGTTTGT       1800                                                                          - GCCTTACATT ATTACTCCTT GCCATTTTCA AGAAAGCATT GCCAGCTCTT CC - #AATCTCCA       1860                                                                          - TCACCTTTGG GCTTGTTTTC TACTTTGCCA CAGATTATCT TGTACAGCCT TT - #TATGGACC       1920                                                                          - AATTAGCATT CCATCAATTT TATATCTAGC ATATTTGCGG TTAGAATCCC AT - #GGATGTTT       1980                                                                          - CTTCTTTGAC TATAACCAAA TCTGGGGAGG ACAAAGGTGA TTTTCCTGTG TC - #CACATCTA       2040                                                                          - ACAAAGTCAA GATTCCCGGC TGGACTTTTG CAGCTTCCTT CCAAGTCTTC CT - #GACCACCT       2100                                                                          - TGCACTATTG GACTTTGGAA GGAGGTGCCT ATAGAAAACG ATTTTGAACA TA - #CTTCATCG       2160                                                                          - CAGTGGACTG TGTCCTCGGT GCAGAAACTA CCAGATTTGA GGGACGAGGT CA - #AGGAGATA       2220                                                                          - TGATAGGCCC GGAAGTTGCT GTGCCCCATC AGCAGCTTGA CGCGTGGTCA CA - #GGACGATT       2280                                                                          - TCACTGACAC TGCGAACTCT CAGGACTACC GGTTACCAAG AGGTTAGGTG AA - #GTGGTTTA       2340                                                                          - AACCAAACGG AACTCTTCAT CTTAAACTAC ACGTTGAAAA TCAACCCAAT AA - #TTCTGTAT       2400                                                                          - TAACTGAATT CTGAACTTTT CAGGAGGTAC TGTGAGGAAG AGCAGGCACC AG - #CAGCAGAA       2460                                                                          - TGGGGAATGG AGAGGTGGGC AGGGGTTCCA GCTTCCCTTT GATTTTTTGC TG - #CAGACTCA       2520                                                                          - TCCTTTTTAA ATGAGACTTG TTTTCCCCTC TCTTTGAGTC AAGTCAAATA TG - #TAGATGCC       2580                                                                          - TTTGGCAATT CTTCTTCTCA AGCACTGACA CTCATTACCG TCTGTGATTG CC - #ATTTCTTC       2640                                                                          - CCAAGGCCAG TCTGAACCTG AGGTTGCTTT ATCCTAAAAG TTTTAACCTC AG - #GTTCCAAA       2700                                                                          - TTCAGTAAAT TTTGGAAACA GTACAGCTAT TTCTCATCAA TTCTCTATCA TG - #TTGAAGTC       2760                                                                          - AAATTTGGAT TTTCCACCAA ATTCTGAATT TGTAGACATA CTTGTACGCT CA - #CTTGCCCC       2820                                                                          - AGATGCCTCC TCTGTCCTCA TTCTTCTCTC CCACACAAGC AGTCTTTTTC TA - #CAGCCAGT       2880                                                                          - AAGGCAGCTC TGTCGTGGTA GCAGATGGTC CCACTTATTC TAGGGTCTTA CT - #CTTTGTAT       2940                                                                          - GATGAAAAGA ATGTGTTATG AATCGGTGCT GTCAGCCCTG CTGTCAGACC TT - #CTTCCACA       3000                                                                          - GCAAATGAGA TGTATGCCCA AAGCGGTAGA ATTAAAGAAG AGTAAAATGG CT - #GTTGAAGC       3060                                                                          #           3087   AAAA AAAAAAA                                               - (2) INFORMATION FOR SEQ ID NO:6:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 945 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                 - GTTNTCCNAA CCAACTTAGG AGNTTGGACC TGGGRAAGAC CNACNTGATC TC - #CGGGAGGN         60                                                                          - AAAGACTNCA GTTGAGCCGT GATTGCACCC ACTTTACTCC AAGCCTGGGC AA - #CCAAAATG        120                                                                          - AGACACTGGC TCCAAACACA AAAACAAAAA CAAAAAAAGA GTAAATTAAT TT - #ANAGGGAA        180                                                                          - GNATTAAATA AATAATAGCA CAGTTGATAT AGGTTATGGT AAAATTATAA AG - #GTGGGANA        240                                                                          - TTAATATCTA ATGTTTGGGA GCCATCACAT TATTCTAAAT AATGTTTTGG TG - #GAAATTAT        300                                                                          - TGTACATCTT TTAAAATCTG TGTAATTTTT TTTCAGGGAA GTGTTTAAAA CC - #TATAACGT        360                                                                          - TGCTGTGGAC TACATTACTG TTNCACTCCT GATCTGGAAT TTTGGTGTGG TG - #GGAATGAT        420                                                                          - TTCCATTCAC TGGAAAGGTC CACTTCGACT CCAGCAGGCA TATCTCATTA TG - #ATTAGTGC        480                                                                          - CCTCATGNCC CTGKTGTTTA TCAAGTACCT CCCTGAATGG ACTGNGTGGC TC - #ATCTTGGC        540                                                                          - TGTGATTTCA GTATATGGTA AAACCCAAGA CTGATAATTT GTTTGTCACA GG - #AATGCCCC        600                                                                          - ACTGGAGTGT TTTCTTTCCT CATCTCTTTA TCTTGATTTA GAGAAAATGG TA - #ACGTGTAC        660                                                                          - ATCCCATAAC TCTTCAGTAA ATCATTAATT AGCTATAGTA ACTTTTTCAT TT - #GAAGATTT        720                                                                          - CGGCTGGGCA TGGTAGCTCA TGCCTGTAAT CTTAGCACTT TGGGAGGCTG AG - #GCGGGCAG        780                                                                          - ATCACCTAAG CCCAGAGTTC AAGACCAGCC TGGGCAACAT GGCAAAACCT CG - #TATCTACA        840                                                                          - GAAAATACAA AAATTAGCCG GGCATGGTGG TGCACACCTG TAGTTCCAGC TA - #CTTAGGAG        900                                                                          #                 945AT TGATCCCAGG AGGTCAAGNC TGCAG                           - (2) INFORMATION FOR SEQ ID NO:7:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 450 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                 - GTTGCAAAGT CATGGATTCC TTTAGGTAGC TACATTATCA ACCTTTTTGA GA - #ATAAAATG         60                                                                          - AATTGAGAGT GTTACAGTCT AATTCTATAT CACATGTAAC TTTTATTTGG AT - #ATATCAGT        120                                                                          - AATAGTGCTT TTTTTTTTTT TTTTTTTTTT TTTTTTTTTT TTTGGGGANA GA - #GTCTCGCT        180                                                                          - CTGTCGCCAG GTTGGAGTGC AATGGTGCGA TCTTGGCTCA CTGAAAGCTC CA - #CCNCCCGG        240                                                                          - GTTCAAGTGA TTCTCCTGCC TCAGCCNCCC AAGTAGNTGG GACTACAGGG GT - #GCGCCACC        300                                                                          - ACGCCTGGGA TAATTTTGGG NTTTTTAGTA GAGATGGCGT TTCACCANCT TG - #GNGCAGGC        360                                                                          - TGGTCTTGGA ACTCCTGANA TCATGATCTG CCTGCCTTAG CCTCCCCAAA GT - #GCTGGGAT        420                                                                          #          450     TGTT CCTGGGCCTC                                            - (2) INFORMATION FOR SEQ ID NO:8:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 516 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                 - GCTCATCATG CTTCACGGGG GAGGCTGTGC GGGAAGAATG CTCCCACACA GN - #ATAAAGAA         60                                                                          - TGCTCCCGCA CAGGATAGAG AATGCCCCCG CACAGCATAG AGAAGCCCCC GC - #ACAGCATA        120                                                                          - GAGAATGCCC CCNCACAGCA TAGAGAAGCC CCCGCACAGC ATAGAGAATG CT - #CTTCACCT        180                                                                          - CTGGGTTTTT AACCAGCCAA ACTAAAATCA CAGAGGSCMA CACATCATTT AA - #GATAGAAA        240                                                                          - TTTCTGTATC TTTTAATTTY TTTCMAAGTA GTTTTACTTA TTTTCAGATT CT - #ATTTCTTT        300                                                                          - ACTAGAATTA AGGGATAAAA TAACAATGTG TGCATAATGA ACCCTATGAA AC - #MAACMMAA        360                                                                          - GCTAGGTTTT TTTCATAGST CTTCTTCCAG ATTGAATGAA CGTCTGTTCT AA - #AATTTAAC        420                                                                          - CCCCCAGGGA AATATTCAGT TAACTATGTT AAAAACCCAG ACTTGTGATT GA - #GTTTTGCC        480                                                                          #      516         ATTA TGTGTGAATG TGTGTC                                     - (2) INFORMATION FOR SEQ ID NO:9:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1726 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                 - GGATCCCTCC CCTTTTTAGA CCATACAAGG TAACTTCCGG ACGTTGCCAT GG - #CATCTGTA         60                                                                          - AACTGTCATG GTGTTGGCGG GGAGTGTCTT TTAGCATGCT AATGTATTAT AA - #TTAGCGTA        120                                                                          - TAGTGAGCAG TGAGGATAAC CAGAGGTCAC TCTCCTCACC ATCTTGGTTT TG - #GTGGGTTT        180                                                                          - TGGCCAGCTT CTTTATTGCA ACCAGTTTTA TCAGCAAGAT CTTTATGAGC TG - #TATCTTGT        240                                                                          - GCTGACTTCC TATCTCATCC CGNAACTAAG AGTACCTAAC CTCCTGCAAA TT - #GMAGNCCA        300                                                                          - GNAGGTCTTG GNCTTATTTN ACCCAGCCCC TATTCAARAT AGAGTNGYTC TT - #GGNCCAAA        360                                                                          - CGCCYCTGAC ACAAGGATTT TAAAGTCTTA TTAATTAAGG TAAGATAGKT CC - #TTGSATAT        420                                                                          - GTGGTCTGAA ATCACAGAAA GCTGAATTTG GAAAAAGGTG CTTGGASCTG CA - #GCCAGTAA        480                                                                          - ACAAGTTTTC ATGCAGGTGT CAGTATTTAA GGTACATCTC AAAGGATAAG TA - #CAATTGTG        540                                                                          - TATGTTGGGA TGAACAGAGA GAATGGAGCA ANCCAAGACC CAGGTAAAAG AG - #AGGACCTG        600                                                                          - AATGCCTTCA GTGAACAATG ATAGATAATC TAGACTTTTA AACTGCATAC TT - #CCTGTACA        660                                                                          - TTGTTTTTTC TTGCTTCAGG TTTTTAGAAC TCATAGTGAC GGGTCTGTTG TT - #AATCCCAG        720                                                                          - GTCTAACCGT TACCTTGATT CTGCTGAGAA TCTGATTTAC TGAAAATGTT TT - #TCTTGTGC        780                                                                          - TTATAGAATG ACAATAGAGA ACGGCAGGAG CACAACGACA GACGGAGCCT TG - #GCCACCCT        840                                                                          - GANCCATTAT CTAATGGACG ACCCAGGGTA ACTCCCGGCA GGTGGTGGAN CA - #AGATGAGG        900                                                                          - AAGAAGATGA GGANCTGACA TTGAAATATG NCGSCAAGCA TGTGATCATG CT - #CTTTGKCC        960                                                                          - CTGTGACTCT CTGCATGGTG GTGGTCGTGG NTACCATTAA GTCAGTCAGC TT - #TTATACCC       1020                                                                          - GGAAGGATGG GCAGCTGTAC GTATGAGTTT KGTTTTATTA TTCTCAAASC CA - #GTGTGGCT       1080                                                                          - TTTCTTTACA GCATGTCATC ATCACCTTGA AGGCCTCTNC ATTGAAGGGG CA - #TGACTTAG       1140                                                                          - CTGGAGAGCC CATCCTCTGT GATGGTCAGG AGCAGTTGAG AGANCGAGGG GT - #TATTACTT       1200                                                                          - CATGTTTTAA GTGGAGAAAA GGAACACTGC AGAAGTATGT TTCCTGTATG GT - #ATTACTGG       1260                                                                          - ATAGGGCTGA AGTTATGCTG AATTGAACAC ATAAATTCTT TTCCACCTCA GG - #GNCATTGG       1320                                                                          - GCGCCCATTG NTCTTCTGCC TAGAATATTC TTTCCTTTNC TNACTTKGGN GG - #ATTAAATT       1380                                                                          - CCTGTCATCC CCCTCCTCTT GGTGTTATAT ATAAAGTNTT GGTGCCGCAA AA - #GAAGTAGC       1440                                                                          - ACTCGAATAT AAAATTTTCC TTTTAATTCT CAGCAAGGNA AGTTACTTCT AT - #ATAGAAGG       1500                                                                          - GTGCACCCNT ACAGATGGAA CAATGGCAAG CGCACATTTG GGACAAGGGA GG - #GGAAAGGG       1560                                                                          - TTCTTATCCC TGACACACGT GGTCCCNGCT GNTGTGTNCT NCCCCCACTG AN - #TAGGGTTA       1620                                                                          - GACTGGACAG GCTTAAACTA ATTCCAATTG GNTAATTTAA AGAGAATNAT GG - #GGTGAATG       1680                                                                          #               1726GAA GAGNAGGTAG NAGGTAACTT GAATGA                          - (2) INFORMATION FOR SEQ ID NO:10:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1883 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                - CNCGTATAAA AGACCAACAT TGCCANCNAC AACCACAGGC AAGATCTTCT CC - #TACCTTCC         60                                                                          - CCCNNGGTGT AATACCAAGT ATTCNCCAAT TTGTGATAAA CTTTCATTGG AA - #AGTGACCA        120                                                                          - CCCTCCTTGG TTAATACATT GTCTGTGCCT GCTTTCACAC TACAGTAGCA CA - #GTTGAGTG        180                                                                          - TTTGCCCTGG AGACCATATG ACCCATAGAG CTTAAAATAT TCAGTCTGGC TT - #TTTACAGA        240                                                                          - GATGTTTCTG ACTTTGTTAA TAGAAAATCA ACCCAACTGG TTTAAATAAT GC - #ACATACTT        300                                                                          - TCTCTCTCAT AGAGTAGTGC AGAGGTAGNC AGTCCAGATT AGTASGGTGG CT - #TCACGTTC        360                                                                          - ATCCAAGGAC TCAATCTCCT TCTTTCTTCT TTAGCTTCTA ACCTCTAGCT TA - #CTTCAGGG        420                                                                          - TCCAGGCTGG AGCCCTASCC TTCATTTCTG ACAGTAGGAA GGAGTAGGGG AG - #AAAAGAAC        480                                                                          - ATAGGACATG TCAGCAGAAT TCTCTCCTTA GAAGTTCCAT ACACAACACA TC - #TCCCTAGA        540                                                                          - AGTCATTGCC CTTACTTGTT CTCATAGCCA TCCTAAATAT AAGGGAGTCA GA - #AGTAAAGT        600                                                                          - CTKKNTGGCT GGGAATATTG GCACCTGGAA TAAAAATGTT TTTCTGTGAA TG - #AGAAACAA        660                                                                          - GGGGAAGATG GATATGTGAC ATTATCTTAA GACAACTCCA GTTGCAATTA CT - #CTGCAGAT        720                                                                          - GAGAGGCACT AATTATAAGC CATATTACCT TTCTTCTGAC AACCACTTGT CA - #GCCCNCGT        780                                                                          - GGTTTCTGTG GCAGAATCTG GTTCYATAMC AAGTTCCTAA TAANCTGTAS CC - #NAAAAAAT        840                                                                          - TTGATGAGGT ATTATAATTA TTTCAATATA AAGCACCCAC TAGATGGAGC CA - #GTGTCTGC        900                                                                          - TTCACATGTT AAGTCCTTCT TTCCATATGT TAGACATTTT CTTTGAAGCA AT - #TTTAGAGT        960                                                                          - GTAGCTGTTT TTCTCAGGTT AAAAATTCTT AGCTAGGATT GGTGAGTTGG GG - #AAAAGTGA       1020                                                                          - CTTATAAGAT NCGAATTGAA TTAAGAAAAA GAAAATTCTG TGTTGGAGGT GG - #TAATGTGG       1080                                                                          - KTGGTGATCT YCATTAACAC TGANCTAGGG CTTTKGKGTT TGKTTTATTG TA - #GAATCTAT       1140                                                                          - ACCCCATTCA NAGAAGATAC CGAGACTGTG GGCCAGAGAG CCCTGCACTC AA - #TTCTGAAT       1200                                                                          - GCTGCCATCA TGATCAGNGT CATTGTWGTC ATGACTANNC TCCTGGTGGT TC - #WGTATAAA       1260                                                                          - TACAGGTGCT ATAAGGTGAG CATGAGACAC AGATCTTTGN TTTCCACCCT GT - #TCTTCTTA       1320                                                                          - TGGTTGGGTA TTCTTGTCAC AGTAACTTAA CTGATCTAGG AAAGAAAAAA TG - #TTTTGTCT       1380                                                                          - TCTAGAGATA AGTTAATTTT TAGTTTTCTT CCTCCTCACT GTGGAACATT CA - #AAAAATAC       1440                                                                          - AAAAAGGAAG CCAGGTGCAT GTGTAATGCC AGGCTCAGAG GCTGAGGCAG GA - #GGATCGCT       1500                                                                          - TGGGCCCAGG AGTTCACAAG CAGCTTGGGC AACGTAGCAA GACCCTGCCT CT - #ATTAAAGA       1560                                                                          - AAACAAAAAA CAAATATTGG AAGTATTTTA TATGCATGGA ATCTATATGT CA - #TGAAAAAA       1620                                                                          - TTAGTGTAAA ATATATATAT TATGATTAGN TATCAAGATT TAGTGATAAT TT - #ATGTTATT       1680                                                                          - TTGGGATTTC AATGCCTTTT TAGGCCATTG TCTCAAMAAA TAAAAGCAGA AA - #ACAAAAAA       1740                                                                          - AGTTGTAACT GAAAAATAAA CATTTCCATA TAATAGCACA ATCTAAGTGG GT - #TTTTGNTT       1800                                                                          - GTTTGTTTGN TTGTTGAAGC AGGGCCTTGC CCTNYCACCC AGGNTGGAGT GA - #AGTGCAGT       1860                                                                          #              1883ACTG CAG                                                   - (2) INFORMATION FOR SEQ ID NO:11:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 823 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                - CAGGAGTGGA CTAGGTAAAT GNAAGNTGTT TTAAAGAGAG ATGNGGNCNG GG - #ACATAGTG         60                                                                          - GTACACANCT GTAATGCTCA NCACTKATGG GGAGTACTGA AGGNGGNSGG AT - #CACTTGNG        120                                                                          - GGTCNGGAAT NTGAGANCAG CCTGGGCAAN ATGGCGAAAC CCTGTCTCTA CT - #AAAAATAG        180                                                                          - CCANAAWNWA GCCTAGCGTG GTGGCGCRCA CGCGTGGTTC CACCTACTCA GG - #AGGCNTAA        240                                                                          - GCACGAGNAN TNCTTGAACC CAGGAGGCAG AGGNTGTGGT GARCTGAGAT CG - #TGCCACTG        300                                                                          - CACTCCAGTC TGGGCGACMA AGTGAGACCC TGTCTCCNNN AAGAAAAAAA AA - #ATCTGTAC        360                                                                          - TTTTTAAGGG TTGTGGGACC TGTTAATTAT ATTGAAATGC TTCTYTTCTA GG - #TCATCCAT        420                                                                          - GCCTGGCTTA TTATATCATC TCTATTGTTG CTGCTCTTTT TTACATTCAT TT - #ACTTGGGG        480                                                                          - TAAGTTGTGA AATTTGGGGT CTGTCTTTCA GAATTAACTA CCTNNGTGCT GT - #GTAGCTAT        540                                                                          - CATTTAAAGC CATGTACTTT GNTGATGAAT TACTCTGAAG TTTTAATTGT NT - #CCACATAT        600                                                                          - AGGTCATACT TGGTATATAA AAGACTAGNC AGTATTACTA ATTGAGACAT TC - #TTCTGTNG        660                                                                          - CTCCTNGCTT ATAATAAGTA GAACTGAAAG NAACTTAAGA CTACAGTTAA TT - #CTAAGCCT        720                                                                          - TTGGGGAAGG ATTATATAGC CTTCTAGTAG GAAGTCTTGT GCNATCAGAA TG - #TTTNTAAA        780                                                                          #823               ATNG TATAAANACC AAAAATAATT GAT                             - (2) INFORMATION FOR SEQ ID NO:12:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 736 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                                - GTCTTTCCCA TCTTCTCCAC AGAGTTTGTG CCTTACATTA TTACTCCTTG CC - #ATTTTCAA         60                                                                          - GAAAGCATTG TCAGCTCTTC CAATCTCCAT CACCTTTGGG CTTGTTTTCT AC - #TTTGCCAC        120                                                                          - AGATTATCTT GTACAGCCTT TTATGGACCA ATTAGCATTC CATCAATTTT AT - #ATCTAGCA        180                                                                          - TATTTGCGGT TAGAATCCCA TGGATGTTTC TTCTTTGACT ATAACAAAAT CT - #GGGGAGGA        240                                                                          - CAAAGGTGAT TTCCTGTGTC CACATCTAAC AAATCAAGAT CCCCGGCTGG AC - #TTTTGGAG        300                                                                          - GTTCCTTCCA AGTCTTCCTG ACCACCTTGC ACTATTGGAC TTTGGAAGGA GG - #TGCCTATA        360                                                                          - GAAAACGATT TTGAACATAC TTCATCGCAG TGGACTGTGT CCTCGGTGCA GA - #AACTACCA        420                                                                          - GATTTGAGGG ACGAGGTCAA GGAGATATGA TAGGCCCGGA AGTTGCTGTG CC - #CCATCAGC        480                                                                          - AGCTTGACGC GTGGTCACAG GACGATTTTC ACTGACACTG CGAACTCTCA GG - #ACTACCGT        540                                                                          - TACCAAGAGG TTAGGTGAAG TGGTTTAAAC CAAACGGAAC TCTTCATCTT AA - #ACTACACG        600                                                                          - TTGAAAATCA ACCCAATAAT TCTGTATTAA CTGAATTCTG AACTTTTCAG GA - #GGTACTGT        660                                                                          - GAGGAAGAGC AGGCACCACC AGCAGAATGG GGAATGGAGA GGTGGGCAGG GG - #TTCCAGCT        720                                                                          #   736                                                                       - (2) INFORMATION FOR SEQ ID NO:13:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 893 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                                - GGATCCGCCC GCCTTGGCCT CCCAAAGTGC TGGGATTACA GGCATGAGCC AC - #CGCTCCTG         60                                                                          - GCTGAGTCTG CGATTTCTTG CCAGCTCTAC CCAGTTGTGT CATCTTAAGC AA - #GTCACTGA        120                                                                          - ACTTCTCTGG ATTCCCTTCT CCTNNWGTAA AATAAGNATG TTATCTGNCC NN - #CCTGCCTT        180                                                                          - GGGCATTGTG ATAAGGATAA GATGACATTA TAGAATNTNG CAAAATTAAA AG - #CGCTAGAC        240                                                                          - AAATGATTTT ATGAAAATAT AAAGATTAGN TTGAGTTTGG GCCAGCATAG AA - #AAAGGAAT        300                                                                          - GTTGAGAACA TTCCNTTAAG GATTACTCAA GCYCCCCTTT TGSTGKNWAA TC - #AGANNGTC        360                                                                          - ATNNAMNTAT CNTNTGTGGG YTGAAAATGT TTGGTTGTCT CAGGCGGTTC CT - #ACTTATTG        420                                                                          - CTAAAGAGTC CTACCTTGAG CTTATAGTAA ATTTGTCAGT TAGTTGAAAG TC - #GTGACAAA        480                                                                          - TTAATACATT CCTGGTTTAC AAATTGGTCT TATAAGTATT TGATTGGTNT AA - #ATGNATTT        540                                                                          - ACTAGGATTT AACTAACAAT GGATGACCTG GTGAAATCCT ATTTCAGACC TA - #ATCTGGGA        600                                                                          - GCCTGCAAGT GACAACAGCC TTTGCGGTCC TTAGACAGCT TGGCCTGGAG GA - #GAACACAT        660                                                                          - GAAAGAAAGG TTTGTTTCTG CTTAATGTAA TCTATGGAAG TGTTTTTTAT AA - #CAGTATAA        720                                                                          - TTGTAGTGCA CAAAGTTCTG TTTTTCTTTC CCTTTTCAGA ACCTCAAGAG GC - #TTTGTTTT        780                                                                          - CTGTGAAACA GTATTTCTAT ACAGTNTGCT CCAANTGNAC AGAGTTACCT GC - #ACNNCGTT        840                                                                          - GTCCNTACTT CCAGAATGCA CAGATGTCTG AGGACAACCA CCTGAGCAAT AC - #T               893                                                                          - (2) INFORMATION FOR SEQ ID NO:14:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 475 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                                - TCAGAAAATA CTTTNGGGCA CATGAGAATC ACATGAGAAC AAGCTGATGC AT - #AATTCCTC         60                                                                          - CTGTGATGGA ATGTAATAGT AATTTAACAG TGTCCTTTCT TTTTAACTGC CT - #CAAGGATA        120                                                                          - CAGCAAAATA AAACAAAAGC AATATGAAGG CTGAGAATAG GTATCAGATT AT - #CATAAAAA        180                                                                          - GTATAGATCA AAAGGAATCT GGTKCTNAGG TTGGCGCAGC AGCCTCTAGA AG - #CGACNAGG        240                                                                          - GAGACTTTTA GAACTACCAT TCTCCTCTAT AAGTGGATCC NANGCCCAGG RA - #AACTTGAT        300                                                                          - ATTGAGNACA ATGGCCTTAC TGAAATAACC TGTGATCCAC TCGGNCTCAT CA - #TCTCCACC        360                                                                          - ACCACCATAA ATTTGATGAG TNCCTATAAT ATTCCANCCA GNGGAAATAC CT - #GGRAGGTT        420                                                                          - ACTGAAAGGC NACNATCAGA CNAAAATAAA GNATACCGTA GGTAAATTCT AC - #AGT             475                                                                          - (2) INFORMATION FOR SEQ ID NO:15:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 180 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                - GTTCTCNAGA TCTCTTCAAA ATTCATTNTG CGCTATAGGA GCTGGGATTA CC - #GCGGGTGC         60                                                                          - TGGAACCAGA CTTGCNCTCC AATGGATCCT CCANACNGGA NGGGGGGTGG AC - #TCACACCA        120                                                                          - TTTACAGGGG GCTCGTAAAG AATCCTGTTT TGANTATTNT NCCGTCAATT AC - #CNCCCCAA        180                                                                          - (2) INFORMATION FOR SEQ ID NO:16:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 457 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                                - AATGTAACMA CMAAACCYCA AACTCCTGNA AGAANATGGT TACTTATNGA TN - #CCATTTNC         60                                                                          - TTTTTNCACT CTCAGACATA AATATAAACM MANTTTCTAC TGTGGRAAAA CA - #TCTNCAGG        120                                                                          - GGNCNTTTAN CCATGATCTC TAGNACNANG GGCTNGTGGN TNGTTTTAAT GT - #CTCTAAGC        180                                                                          - NACTNGACTA GTTTCTCTTN CACTGAGNAA ACTGCNACAA GTNNTTNCTN CT - #GNATCTGN        240                                                                          - ACTGNAATGC TAAGTTNCAA GTNCCAATGA GCTNGTGANT TANYCTTTAT TT - #NAMCNAAA        300                                                                          - GTNNTTAATC ANCCNCAGTG TTACTTTGNA AAGCTNCTCC CTGGACAGGC GG - #CCCNACTT        360                                                                          - CTAATGTTAT GAATGGGCTG GAGNANCCTC NACNTGAGTT TNNWAAGGNT CA - #ACANCCAA        420                                                                          #     457          CTCT AAATTCCAAC CNATAAT                                    - (2) INFORMATION FOR SEQ ID NO:17:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 373 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                                - ATCTGTGCTA GGTAGTGTAC TAATCATTCA GTTTATCTCA TTTAATCTNN AT - #GNAACTCT         60                                                                          - AAGTCATTCG CTNTGANCNA CACATAACAG ATCTCGCAAC TGNAGTTTAG CG - #AGGCCAGT        120                                                                          - TAATTTKCCA AAGNTCATAA TNCTAAGNAG TTCTAGNATG GAGATTCMAA GT - #CCNACTGT        180                                                                          - TTAGTCAAGA GACCCTACTG TTAACTAGTA CCTTTACACT ACTAACTGGG TA - #ANCCATAA        240                                                                          - NCAATTAATG ATAAAGATTG AGATTACTKC CACATTCTCA CTGGTTATAA AT - #TAAAACNT        300                                                                          - CAAATAAAAA NTCTTGGCAC TTCTATGGTA ATATTTTTAT TAGGATAAAC TT - #TCAAGNAG        360                                                                          #     373                                                                     - (2) INFORMATION FOR SEQ ID NO:18:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 422 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                                - CCCACACTGN TGGGCCATGG AAGCCATGAG TGTACCACAT GGCCCTGTCC CA - #CTGGCCAC         60                                                                          - AGTNGATTGG TTGGNTCGGG AGTAGTCACC TGATTCAAGN TGGGCCAATC AG - #ATCCTACC        120                                                                          - TCCANGGGGT TNGGAATTAG AAAACAGTGA CCCTAGYTAG TNTAGGCNAC TT - #GAACTGGA        180                                                                          - GGGCCCATAC ATTCAGGAGC CTTATGGGGC CATGTACACA TGGAAGCAGG AA - #GANTGAAG        240                                                                          - GAGGGAGAAG TAGAGGCCAG AAACCCACCT GGGTTCCTGT TTCCCAATGN TA - #AGTCCCTG        300                                                                          - CCATGTYCCT GCTCTTCCTG TGGTTNGGAT CTTCAAAGGT TGCTCAAATT NG - #GGGCAGTG        360                                                                          - GCCCTGGCAG CTTTTCAAAT CCTYCCCATT TTTATTGAAG CTGAAAGACC CT - #TGACTAGA        420                                                                          #             422                                                             - (2) INFORMATION FOR SEQ ID NO:19:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 395 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                                - ATTGTTATTT TTCGTCACTA CCTCCCCGGG TCGGGAGTGG GTAATTTGCG CG - #CCTGCTGC         60                                                                          - CTTCCTTGGA TGTGGTAGCC GTTTCTCAGG CTCCCTCTCC GGAATCGAAC CC - #TGATTCCC        120                                                                          - CGTCACCCGT GGTCACCATG GTTAGGCACG GCGACTACCA TCGAAAGTTA AT - #AGGGCAGA        180                                                                          - TCTCGAGAAT TCTCGAGATC TCCNTCMAAT TATTACTTCA NTTKCGGTAG TG - #ATCAGNAC        240                                                                          - NAGGCAGTTC TATTGATTTC TCTCCTTTCA TTCTGAGTTT CTCCATAAAT TA - #ATTGGACC        300                                                                          - TAATCATGTT TKNAATCCTG TCTTTTAGGG GGNANTTGNA CTNTCAAGTG TT - #TAAAGGGA        360                                                                          #      395         NTGG ATTGGAGTGA GAGCA                                      - (2) INFORMATION FOR SEQ ID NO:20:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 487 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                                - CAGANTTTCT GGGTNAAAAG GACCTNANAC ATAATATAGT GGACTTNCAA TA - #AACACTTA         60                                                                          - CCAAATGGAN AAATGAACCC CTGGTCACCC CGATCTCACT AGTNCCTNCC CT - #GAAACCCG        120                                                                          - ANANATCTGA GTCCTTTTCT CCTTTACTAA CCCTTNCTCC AATCCTGCTC AT - #GGGAATTA        180                                                                          - ANGNTGTAAA ATANGCCTGG GGNACCTCGG RCCTCTNCCC TGGGNTCTGT GG - #GTGGGAGN        240                                                                          - ACTGTGGAAG CCGTWTCAAT CGCCCCCACC TATGAGAGCC TTTCTNCAGG GC - #CAGCCATG        300                                                                          - AACGTCCCCC ATGTNATCAG NATCTNCAGG CTACTGCTGT CCTTCYTGGA TW - #TTTAACCT        360                                                                          - GGRGGCGGGC CAGGGACAGA AAARGGAGGT GGCAAGATCC TTGAACAAAA GG - #AGCTATAA        420                                                                          - AAGGGCGTTG GGGGAAGCAA GGCAAACGGC AGATTAAACA AGCAGGCACC TC - #AAGGAAAC        480                                                                          #         487                                                                 - (2) INFORMATION FOR SEQ ID NO:21:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 500 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                                - CTCGAGATCT GGCCCATCAT TTAGTTTTAT NGCTTGNAGT NTNTAGNAGA TA - #AAACATCC         60                                                                          - ACGTGGATCT NCTCTTAGAG AAATCAANTA CTTTAGGNAT NTGATAGTCA GA - #GANTGGNT        120                                                                          - ATCAAATNGA AAGGNATNTN GGTNGANCAG TTAGTTNGYN CCNTTNGNNG AG - #ACCACTGG        180                                                                          - GNTGTNGASA CCAGATTCMK GGGTNCNAAT CTTANGGTAA TCTNAGAGCC AA - #CACATGGG        240                                                                          - TCATNTTATS CCCCAAACTT AGCCACATCT BGTGGGGYTA TGGNGTCACC CC - #AAGAGCAG        300                                                                          - GAGGAGCATG GNTGGATGGA AATCCATCTC CACCACTGGA ACCCCAAWTT CT - #GAATGNAT        360                                                                          - CACCTGTTAG AGTTTCTTGT YCATAAAATA GCAGGGAATT TAGGAATTTA GT - #TTTTTTTT        420                                                                          - AATAGTTTGG GCCTTTTATC CACACTCTCA GGAGCTTAGG ATACTTTTCT CC - #TTCAGCTC        480                                                                          #500               TGGA                                                       - (2) INFORMATION FOR SEQ ID NO:22:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 406 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                                - TCGAGATCTG TGGTAGTNAC ATGATATTCT GGCAMCTACT TTCATTATCA CC - #TTTATTAA         60                                                                          - AATAAATTTA AAGAAAAATG GCAGTATGTT TCTGTGRAGN CCACGAGTAC TC - #ATTTTAAA        120                                                                          - GGACTCMAGA GTTNCAGRNA AGTAAAAAGR AAAGAGTAAA ATCATTTTCT AA - #NTYTYWYY        180                                                                          - TTCCAGAAAT AACGATGTTG AGCATTAAGT GGACTTCATT TCATACTCTT TC - #MMAGNTTA        240                                                                          - TGTAGGCATA WAWATGTGTG TGTATATACA TATATATGGG TACATCCTTA GA - #GAAGTTGG        300                                                                          - CTGGCTAGAT AGACACACNT NAAAAATGGR ATCATACTCT AATKCCATTT NN - #ANTTTANA        360                                                                          #                406CNC TGTNCTTATA NACAGAGTAA NTGAAA                          - (2) INFORMATION FOR SEQ ID NO:23:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 289 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                                - GACCCAGTAA AACTTATCTC ATGAGCATAA GGCTGAATGG GATTGACAGC CT - #ACAGAACC         60                                                                          - CGGATTTTAT CATGAGGGCA TTAGTGGGGG TTGGGGGTTA GGTACTGAAA GT - #TTAAGGAG        120                                                                          - GTGAAAGGAA AGCAACTTGT GCCTTACAGG GTCAAGCTAG GTCAAGGAAA TT - #CCCAGGAG        180                                                                          - CGTGTGGAAG CTCTCTACCT GATAGGTGAG CTCAAGCTTA TGACCGCCCA AG - #CTTCTCCC        240                                                                          #              289CTGCT TCCTCTTGAT TGACTTCCAC AGCAAGGTC                       - (2) INFORMATION FOR SEQ ID NO:24:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 367 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                                - CCATCAGGAT TTACTGAGTA AAAATCTCAG GTNTTAACCA TGCCCCTAAA AT - #GTGCTATN         60                                                                          - CCAAAGAGGA ACAGGTTACT TGGGAGGAAA AAAGCTGCCT GGGNAACTCC CC - #NCAAATGT        120                                                                          - TTATTTTAAA TAAAAATGGT NGATGGAAAT ATTTTNTAAA AGAACTTGGG GT - #NTAATATG        180                                                                          - GNATACTGCC CATCAAACAA AAAAGGAAAT AAAACTTCNT TCCCATTTAT AA - #TAAGTTNC        240                                                                          - CCACCCTTTA CTATCAAGAT TACAACTTAT TGACCTTTTA TGCTNGCTNG GT - #TTTTTTGG        300                                                                          - GACTGCCTAA TCCAATGTTT AAATTTTCTA NGTCTGNATT TCAATGTGGG TA - #GGAGTNAT        360                                                                          #         367                                                                 - (2) INFORMATION FOR SEQ ID NO:25:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 425 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                                - GAGTATCTGA CAGGTAAGAT TGCTTTTTAA AGTTGTTTTA AATGCATTAC AT - #GACTGAGA         60                                                                          - AAAGAAAAAT GCACATTTTA TTGTTGCAGT TTAAAATTTC ATTTNGNGTG AA - #ACTAAACG        120                                                                          - TGAAACAAAA GGGATAAATG TGTTTTGNTT TTGTTTTGGT TTTACCTGTT TG - #GGGTATTT        180                                                                          - TTTTCTGAGT TTGTGTAGAA ACCCGTGTGG NTACACTGGG TAATCTTGTC AG - #GGNTACMA        240                                                                          - AMCTTGGGTC TTGANTTTGG TTANTTGGNT TTANTTGGTG NACCCATGTA CT - #TGCTCTTC        300                                                                          - CNTCCCAGAA ACATAGCTTG GTAGGCNAGG GTTAANCCAG TGTCGGCGAN CC - #CATGTCCC        360                                                                          - TANCACAGCA TCTTGTAAGT TTAATGCACA ATCGTTCCNT CCCAGGATGG AN - #TTATCATT        420                                                                          #           425                                                               - (2) INFORMATION FOR SEQ ID NO:26:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 2377 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                                - GAGAGGCGCA GGAGCCACAA ATAAAGCAAG AGCCAGAATC AGAAGNGGAG GA - #AGAAGAAA         60                                                                          - AGCAAGAAAA AGRAGRAANA CGAGAAGAAC CCATGGRAGA GGAAGAGGAN CC - #AGANCMAA        120                                                                          - AGCCTTGTCT GAAACCTACT CTGAGGCCCA TCAGCTCTGC TCCATCTGTT TC - #CTCTGCCA        180                                                                          - GTGGNAATGC NACACCTAAC ACTCCTGGGG ATGAGTCTCC CTGTGGTATT AT - #TATTCCTC        240                                                                          - ATGRAAACTC ACCAGATCAA CAGCAACCTG AGGAGCATAG GCCMAAAATA GG - #ACTAAGTC        300                                                                          - TTAAACTGGG TGCTTCCAAT AGTCCTGGTC AGCCTAATTC TGTGAAGAGA AA - #GAAACTAC        360                                                                          - CTGTAGATAG TGTCTTTAAC AAATTTGAGG ATGAAGACAG TGATGACGTA CC - #CCGAAAAA        420                                                                          - GGAAACTGGT TCCCTTGGAT TATGGTGAAG ATGATAAAAA TNCAACCAAA GG - #CACTGTAA        480                                                                          - ACACTGAAGA AAAGCGTAAA CACATTAAGA GTCTCATTGA GAAAATCCCT AC - #AGCCAAAC        540                                                                          - CTGAGCTCTT CGCTTATCCC CTGGATTGGT CTATTGTGGA TTCTATACTG AT - #GGAACGTC        600                                                                          - GAATTAGACC ATGGATTAAT AAGAAAATCA TAGAATATAT AGGTGAAGAA GA - #AGCTACAT        660                                                                          - TAGTTGATTT NGTTTGTTCT AAGGTTATGG CTCATAGTNC ACCCCAGAGC AT - #TTTAGATG        720                                                                          - ATGTTGCCAT GGTACTTGAT GAAGAAGCAG AAGTTTTTAT AGTCAAAATG TG - #GAGATTAT        780                                                                          - TGATATATGA AACAGAAGCC AAGAAAATTG GTCTTGTGAA GTAAAACTTT TT - #ATATTTAG        840                                                                          - AGTTCCATTT CAGATTTCTT CTTTGCCACC CTTTTAAGGA CTTKGAATTT TT - #CTTTGTCT        900                                                                          - TKGAAGACAT TGTGAGATCT GTAATTTTTT TTTTTTGTAG AAAATGTGAA TT - #TTTTGGTC        960                                                                          - CTCTAATTTG TTGTTGCCCT GTGTACTCCC TTGGTTGTAA AGTCATCTGA AT - #CCTTGGTT       1020                                                                          - CTCTTTATAC TCACCAGGTA CAAATTACTG GTATGTTTTA TAAGCCGCAG CT - #ACTGTACA       1080                                                                          - CAGCCTATCT GATATAATCT TGTTCTGCTG ATTTGTTTCT TGTAAATATT AA - #AACGACTC       1140                                                                          - CCCAATTATT TTGCAGAATT GCACTTAATA TTGAAATGTA CTGTATAGGA AC - #CAACATGA       1200                                                                          - ACAATTTTAA TTGAAAACAC CAGTCATCAA CTATTACCAC CCCCACTCTC TT - #TTCATCAG       1260                                                                          - AAATGGCAAG CCCTTGTGAA GGCATGGAGT TTAAAATTGG AATGCAAAAA TT - #AGCAGACA       1320                                                                          - ATCCATTCCT ACTGTATTTC TGTATGAATG TGTTTGTGAA TGTATGTGTA AA - #AGTCTTTC       1380                                                                          - TTTTCCCTAA TTTGCTTTGG TGGGGTCCTT AAAACATTTC CCAACTAAAG AA - #TAGAATTG       1440                                                                          - TAAAGGAAAA GTGGTACTGT TCCAACCTGA AATGTCTGTT ATAATTAGGT TA - #TTAGTTTC       1500                                                                          - CCAGAGCATG GTGTTCTCGT GTCGTGAGCA ATGTGGGTTG CTAACTGTAT GG - #GGTTTTCT       1560                                                                          - TATTAATAAG ATGGCTGCTT CAGCTTCTCT TTTAAAGGAA TGTGGATCAT AG - #TGATTTTT       1620                                                                          - CCTTTTAATT TTATTGCTCA GAAATGAGGC ATATCCCTAA AAATCTCGGA GA - #GCTGTATT       1680                                                                          - TAATGCATTT TTGCACTAAT TGGTCCTTAG TTTAATTCTA TTGTATCTGT TT - #ATTTAACA       1740                                                                          - AAAAATTCAT CATATCAAAA AGTGTAAGTG AAAACCCCCT TTAAAACAAA AC - #AAAAAAAT       1800                                                                          - GAAATAAAAT TAGGCAAATT GACAGACAGT GAGAGTTTTA CAAACATGAT AG - #GTATTCTG       1860                                                                          - CTCGGCAATT TGTAAGTTTA CATGTTATTT AAGGATAAAG GTAAATCATT CA - #AGGCAGTT       1920                                                                          - ACCAACCACT AACTATTTGT TTTCATTTTT GTCTTGTAGA AGGTTTATAT CT - #TGTTTTAC       1980                                                                          - CTTGGCTCAT TAGTGTTTAA AAATGTACTG ATGATGTGCT TAGAGAAATT CC - #TGGGGCTT       2040                                                                          - TCTTCGTTGT AGATCAGAAT TTCACCAGGG AGTAAAATTA CCTGAAAACG TA - #AGAAGTTT       2100                                                                          - TAAACAGCTT TCCACACAAA TTAGATGCAA CTGTTCCCAT GTCTGAGGTA CT - #TATTTAAA       2160                                                                          - AGAAAGGTAA AGATTGGCCT GTTAGAAAAA GCATAATGTG AGCTTTGGAT TA - #CTGGATTT       2220                                                                          - TTTTTTTTTT TAAACACACC TGGAGAGGAC ATTTGAAAAC ACTGTTCTTA CC - #CTCGAACC       2280                                                                          - CTGATGTGGT TCCATTATGT AAATATTTCA AATATTAAAA ATGTATATAT TT - #GAAAAAAA       2340                                                                          #    2377          CCTG CGGCCGCAAG GGAATTC                                    - (2) INFORMATION FOR SEQ ID NO:27:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 489 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                                - ATTGGAGCTC CACCGCGGTG GCGGCCGCTC TAGNAACTAG TGGATCCCCC GG - #GCTGCAGG         60                                                                          - AATTCTCGAG ATCTCCCCCA AGTAAATGAA TGAAAAAAAG AACAGCAACA AT - #AGAGATGA        120                                                                          - TATAATAAGC CAGGCATGGA TGACCTTATA GCACCCTGTA TTTATACAGA AC - #CACCAGGA        180                                                                          - GGATAGTCAT GACAACNATG ACACTGATCA TGATNCCAGC ATTCAGAATT GA - #GTNCAGGG        240                                                                          - CTCTCTGGCC CACAGTCTCG GTATCTTCTG TGNATGGGGT ATAGATTARC TG - #TCCATCCT        300                                                                          - TCCGGGNATA AAANCTGACT GACTTAATGG TANCCACGAC CACCACCCAT KC - #AGAGAGTC        360                                                                          - ACAGGGACMA AAGAGCATGA TCAACATGCT TGGCNCCATA TTTCAATNTC AN - #CTCCTCAT        420                                                                          - CTTCTTCCTC ATCTTNCTCC ACCACCTNCC GGGAGTTAAC CCTGGGGTCG TC - #CATTAGAT        480                                                                          #        489                                                                  - (2) INFORMATION FOR SEQ ID NO:28:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 2307 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                                - AGGGTGCTTC AGTGTGGCTG ACACAGCAGC ATGGTCTTGA CAAGTTTTCT TC - #ATCCTACC         60                                                                          - ACAAAATCCC AGTTGGTAAT AGAGACTTTA CTCCTACCTA TCAAAACCAC AA - #AATGTCCC        120                                                                          - ATTAGGGGGG GACATGTTGT ACATGTTAGG ATCATTCAAA TAACCAAGAT TA - #TAAGGTGA        180                                                                          - GGAAAGATGC CCCTAACTGA TTCTTTTGTC TCTCATCTTG TTGGTTCCAG GG - #ACCGAGTG        240                                                                          - GGGTCAATCT TCTGGTSSTG CCTCTCCAGG TCTCTTCCAG GCCGGTCATA GA - #CGTACTCC        300                                                                          - CTCTGAGGCC GACCGATGGT TAGAAGAGGT GTCTAAGAGC GTCCGGGCTC AG - #CAGCCCCA        360                                                                          - GGCCTCAGCT GCTCCTCTGC AGCCAGTTCT CCAGCCTCCT CCACCCACTG CC - #ATCTCCCA        420                                                                          - GCCAGCATCA CCTTTCCAAG GGAATGCATT CCTCACCTCT CAGCCTGTGC CA - #GTGGGTGT        480                                                                          - GGTCCCAGCC CTGCAACCAG CCTTTGTCCC TGCCCAGTCC TATCCTGTGG CC - #AATGGAAT        540                                                                          - GCCCTATCCA GCCCCTAATG TGCCTGTGGT GGGCATCACT CCCTCCCAGA TG - #GTGGCCAA        600                                                                          - CGTWTTTGGC ACTGCAGGCC ACCCTCAGGC TGCCCATCCC CATCAGTCAC CC - #AGCCTGGT        660                                                                          - CAGGCAGCAG ACATTCCCTC ACTACGAGGC AAGCAGTGCT ACCACCAGTC CC - #TTCTTTAA        720                                                                          - GCCTCCTGCT CAGCACCTCA ACGGTTCTGC AGCTTTCAAT GGTGTAGATG AT - #GGCAGGTT        780                                                                          - GGCCTCAGCA GACAGGCATA CAGAGGTTCC TACAGGCACC TGCCCAGTGG AT - #CCTTTTGA        840                                                                          - AGCCCAGTGG GCTGCATTAG AAAATAAGTC CAAGCAGCGT ACTAATCCCT CC - #CCTACCAA        900                                                                          - CCCTTTCTCC AGTGACTTAC AGAAGACGTT TGAAATTGAA CTTTAAGCAA TC - #ATTATGGC        960                                                                          - TATGTATCTT GTCCATACCA GACAGGGAGC AGGGGGTAGC GGTCAAAGGA GC - #MAAACAGA       1020                                                                          - YTTTGTCTCC TGATTAGTAC TCTTTTCACT AATCCCAAAG GTCCCAAGGA AC - #AAGTCCAG       1080                                                                          - GCCCAGAGTA CTGTGAGGGG TGATTTTGAA AGACATGGGA AAAAGCATTC CT - #AGAGAAAA       1140                                                                          - GCTGCCTTGC AATTAGGCTA AAGAAGTCAA GGAAATGTTG CTTTCTGTAC TC - #CCTCTTCC       1200                                                                          - CTTACCCCCT TACAAATCTC TGGCAACAGA GAGGCAAAGT ATCTGAACAA GA - #ATCTATAT       1260                                                                          - TCCAAGCACA TTTACTGAAA TGTAAAACAC AACAGGAAGC AAAGCAATGT CC - #CTTTGTTT       1320                                                                          - TTCAGGCCAT TCACCTGCCT CCTGTCAGTA GTGGCCTGTA TTAGAGATCA AG - #AAGAGTGG       1380                                                                          - TTTGTGCTCA GGCTGGGAAC AGAGAGGCAC GCTATGCTGC CAGAATTCCC AG - #GAGGGCAT       1440                                                                          - ATCAGCAACT GCCCAGCAGA GCTATATTTT GGGGGAGAAG TTGAGCTTCC AT - #TTTGAGTA       1500                                                                          - ACAGAATAAA TATTATATAT ATCAAAAGCC AAAATCTTTA TTTTTATGCA TT - #TAGAATAT       1560                                                                          - TTTAAATAGT TCTCAGATAT TAAGAAGTTG TATGAGTTGT AAGTAATCTT GC - #CAAAGGTA       1620                                                                          - AAGGGGCTAG TTGTAAGAAA TTGTACATRA GATTGATTTA TCATTGATGC CT - #ACTGAAAT       1680                                                                          - AAAAAGAGGA AAGGCTGGAA GCATGCAGAC AGGATCCCTA GCTTGTTTTC TG - #TCAGTCAT       1740                                                                          - TCATTGTAAG TAGCACATTG CAACAACAAT CATGCTTATG ACCAATACAG TC - #ACTAGGTT       1800                                                                          - GTAGTTTTTT TTAAATAAAG GAAAAGCAGT ATTGTCCTGG TTTTAAACCT AT - #GATGGAAT       1860                                                                          - TCTAATGTCA TTATTTTAAT GGAATCAATC GAAATATGCT CTATAGAGAA TA - #TATCTTTT       1920                                                                          - ATATATTGCT GCAGTTTCCT TATGTTAATC CTTTAACACT AAGGTAACAT GA - #CATAATCA       1980                                                                          - TACCATAGAA GGGAACACAG GTTACCATAT TGGTTTGTAA TATGGGTCTT GG - #TGGGTTTT       2040                                                                          - GTTTTATCCT TTAAATTTTG TTCCCATGAG TTTTGTGGGG ATGGGGATTC TG - #GTTTTATT       2100                                                                          - AGCTTTGTGT GTGTCCTCTT CCCCCAAACC CCCTTTTGGT GAGAACATCC CC - #TTGACAGT       2160                                                                          - TGCAGCCTCT TGACCTCGGA TAACAATAAG AGAGCTCATC TCATTTTTAC TT - #TTGAACGT       2220                                                                          - TGGCGCTTAC AATCAAATGT AAGTTATATA TATTTGTACT GATGAAAATT TA - #TAATCTGC       2280                                                                          #           2307   GTTC ATGGTAG                                               - (2) INFORMATION FOR SEQ ID NO:29:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 343 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                                - GGCAGCTATT TACATGGCCT CACAGGCATC AGCTGAAAAG AGGACCCMAA AA - #GAAATTGG         60                                                                          - AGATATTGCT GGTGTTGCTG ATGTTACAAT CAGRCAGTTC TATAGACTGA TC - #TATCCTCG        120                                                                          - AGCCCCAGAT CTGTTCCTTA CAGACTTCMA ATTKGACACC CCAGTGGACA AA - #CTACCACA        180                                                                          - GCTATAAATT GAGGCAGYTA ACGTCMAATT CTTGANNACM AAACTTKNCC TG - #TTGTACAT        240                                                                          - AGCCTATACM AAATGCTGGG TTGAGCCTTT CATAAGGNAA AACMNAAGAC AT - #GGNTACGC        300                                                                          #343               ACTT ATTGCTTGGC ATTCTTGTAT GTA                             - (2) INFORMATION FOR SEQ ID NO:30:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 363 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                                - AAAGGGCTAA CCAGCCACTG CACCAAAATT AGTCCTTACA TTATAATACT CT - #GGCCATTG         60                                                                          - GAAGAGAAAA ATGGGAAAAT TCAACAATTT GAAAGACTAT GATCCCTCTG GC - #TCATGATC        120                                                                          - TACTGACCAG AATGAAGTCC TGAAGGATTT CCTTCTGTTA TGTTATCTAC CC - #AGCTAATC        180                                                                          - TCAAACAAGA GGAGCTGGAA AGAACAAAGC CCCATGAAGC TACCCCTAGA CC - #CAGAAAGC        240                                                                          - CAAGAACAGG GCCAAGAAAA TGAACAGCAG ACAAGCCTGA AATAGAAGTG GN - #ACAGACAT        300                                                                          - GTGGNAAGAC CAAGTACACC CAGTTNGGTG GTAAAGATTC CGATATCAAG CT - #TATCGATA        360                                                                          #            363                                                              - (2) INFORMATION FOR SEQ ID NO:31:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 362 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                                - AGTACATGGT TTCTTGNCCA CCCCASCCAC CTTTCCCCAT CTCTACCGGY TG - #ATAGTCTC         60                                                                          - TCAGNTAGTA GACCTTTTCT NGTTTAGRCA GGGCCACNTT TTTAAAAACT CC - #AGACGGGT        120                                                                          - ACCCTCCATG TKGMAGGCGA CGTGGCCCTG GATCACTCAA CTGANTGTCA TN - #KGANTGGT        180                                                                          - GCCCCCAGAG TGAGGACAAT GGTGNAGCCC TCCTAAGGCC CTNCCTGAGT GT - #CCCTCCTT        240                                                                          - CATGAAGATG ATTCTGAGGN TTCCCAGGCC TNCACCCTTC TTKGAAARCC CA - #TAGNAGTT        300                                                                          - CATATGNACT NCTCTNCTAT GCTCACCAAA CTCTNCCTTC ATCATACTTG GG - #GGATGTGT        360                                                                          #             362                                                             - (2) INFORMATION FOR SEQ ID NO:32:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 475 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                                - GTGCATGTAA TTACAGTTAC GATATATGAA ACGTACAAAA TATTATGAGT AT - #ATAATATG         60                                                                          - GGGAGACTTA ATCTAGTTTG GGGGATCAGG GCACATTTCT CTAAGAAAGT GA - #CATTTGAA        120                                                                          - TTGAGCTCTG AAGGATAAAT AGACATTACC CAGAAGAATA AAATGATGGG GA - #AGAAGGAG        180                                                                          - GACATTTTCC GTAGATTTCC AGTGGCCCCN CTTGATCCCT TATCCACTCA TC - #ACTNAGGA        240                                                                          - GGATATTAAA TKCTATAGAA ATGGRAGRAA GACMMAAAGA GACCCTNATA TC - #TCGAGAGG        300                                                                          - ATCCAGCMAA ATTCCAAGAG ACACAACAWT AAGAAACTNG GAAGGAAGAG AA - #AAGGCMMN        360                                                                          - NNAGGNAAAA GAAAGACAAG GAAATTNWNN NAGNACGGAG AGAAAGAGAG AG - #GGAGCGTN        420                                                                          - NAAGGGNACG AGAAAGGCGA GNACGGGGAC GAGAAAGGGN AAGAGNACGT AA - #ACG             475                                                                          - (2) INFORMATION FOR SEQ ID NO:33:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 346 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                                - GGAAATAAAT GAGATCTCAG TGGTGGTATG GATTGGACTG ATCTCTGTAA CT - #GTGTNTGG         60                                                                          - AAAAAGGACC GGAAAATGAA AGCCAGATCC CAGTAAGGGG TAGAGAGGGG CC - #AAGAGAAC        120                                                                          - TGAACATCTG GGCTGCCGGA GAAATCAAAG TCTAGGAAGT AAGAGGTAAG AG - #TGTACTAC        180                                                                          - AGGGGACATA CCCCAATCTC TTGGTTCCCT CCCTCTNCCT TCCTCTCCCA GA - #GACCCAGG        240                                                                          - TCCCTGGGAC TATNTTGGAT CTGTCTCTGA AGCTGAAAAA CAAAAGGCAG AG - #GAGACAGT        300                                                                          #                346TCT CAAGCCAGCT TGGTCAGAAN TCCTAA                          - (2) INFORMATION FOR SEQ ID NO:34:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 433 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                                - AAATCCAGTG CAGGCAACAT TATGTGGAAA TAGAAACAGG GCTCCTGCTA GG - #AGATTGAN         60                                                                          - ATTCTGGCTT TCCTTTGGAA CCCCTCACTG ACTCATCGCC CCTGAANCAG GA - #NCCANCAG        120                                                                          - GTNCCAAGGC TCCCCTGCTC CTNTCCCTNC CCCAGGGCGA GATAGGAARC CG - #GAARCCTG        180                                                                          - GGCAGGCTGA RCCCANCCGA CTGGAACCAG GGNAGANCCT GTGGGTGGGT GG - #NAGGGAGG        240                                                                          - GAAGGAGGCC AGATTCCTCC AGAACTGGGG RAGAGAACAG GTTTTGGAAG TT - #GGGGGAGG        300                                                                          - GTTTGGGTTT CACAGTGATG GTTTCATGAN ACCCTGGAGG GTTNCACACT CC - #TGGTKCAN        360                                                                          - TTTTGNTANT CGTNCTTTGA ANACARNCCG CTTCCTTTCA ACCCTCCNCN TA - #AAAAGTTT        420                                                                          #     433                                                                     - (2) INFORMATION FOR SEQ ID NO:35:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 350 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                                - ACCAAGAGCC CCCAGTTTAT GNTAACTCTC ATGACAAACA CAATTTTAGT AC - #CTCTCACT         60                                                                          - ACCAACTATC CAGGAACCAG GANTCACCTA TTACTACGGT TCCAGCAGAA TG - #GGAATCCC        120                                                                          - ATTCTCGGAT ATCCAGGGTA AATCCCTGAC CATGTGAGAG GAATCCTAGT GC - #CCCAACAA        180                                                                          - CCTCACCCCC TGACTCCTCC TCAANGGCTC TGCCAAGTCA ACAAAAAAAT CC - #TCTACATT        240                                                                          - TACACTATCT GTAAAGCCAA AGACCAGCGT CAACCTAAAT GTCCATCAAT AA - #GGGAATGG        300                                                                          #             350ATTATG CAGCTGTAGG AAGGAATGAA GAATGTCTAT                      - (2) INFORMATION FOR SEQ ID NO:36:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 512 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                                - AAAGGGAACA AAAGCTGGTA CCGGGCCCCC CCTCGAGGTC GACGGTATCG AT - #AAGCTGGA         60                                                                          - TATCGAATCC TCGAGATCTA CCTAAAAAAA AAAAATTAAC TTCCCAAATG TG - #GGAGTCTA        120                                                                          - CTCTGTTCCC TCCTNGTNTT TATTNCTGTN TACTTTYCTA ANATGGTTAA AA - #TGTGTAAN        180                                                                          - CAATATGTGT CCTTTNACTN KGGKGTGAAC ATTTTTYCTA TTATAAATYC TW - #AGAAAATA        240                                                                          - TTNCTATGGN TATGAGATAT TKGATTCCAA GTGCCTKGTA ATTTACTYCT CA - #AATGTCCC        300                                                                          - TGATGTKGGA NATTKGTTNC TAGTGTTYCA CTATTTAAAA AAACAGNAAT AT - #CTGTCTNT        360                                                                          - ATGCTNAGAG CTTNTYCAGT TTYCAAATTA TTNCCTTAGG GTAAAATCCT AG - #AAGTAGAA        420                                                                          - TTTTTGGGGC AAATTATCTA CATATTTATA ATTGTCTTGG TATTCCAAAT CT - #CGTTTTCC        480                                                                          #         512      TTGT ACTTAACACC AG                                         - (2) INFORMATION FOR SEQ ID NO:37:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 450 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                                - ATTTAAGATG ACTGGGGGTC TCTNCCTAAT CCCATACTCC ACTGGAGAGG AN - #AAGTGGGA         60                                                                          - AAGGTTGGTC TAGTTARGGT NGNTGGGGAC CCTCCCAAGA GCTGNAGAAG CA - #GAGATAAG        120                                                                          - NAGAGCCTNC TNCTAAATCC ACATGGNCCT YCCAAGGNTC TCATCCTCTA GG - #ACCTACCA        180                                                                          - CTNCTCAGTC TACTTACTTG TCTYCTGANA TGCTTTCTNG AGGGGNAGAA AA - #CAAAGGAA        240                                                                          - GAGTAATAAC AAGCAGNAGA AACTGCAGAG AATGNAAAAT AAGTCCATAG GA - #GAATGTTG        300                                                                          - NAAATAGAAT CATCCNCCTT TACATATTGT CACTCCAGGA AAACTGCCAA GA - #ACCACTCA        360                                                                          - TTCCTCTAGA TACAMTTCCT GTAGGATCCY CCCAGACTTC CTCCCTTAAG CA - #CGTCAGTA        420                                                                          #          450     TTCA TTTCAACCCT                                            - (2) INFORMATION FOR SEQ ID NO:38:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 766 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                                - CGAGATCTGC CCCAGCCCAC ATTTCCTTTG TTGAATGAGT AGAGAAGACT GA - #GAAGTATC         60                                                                          - ACTCACCCGT GATGTGGTTT GTCCCTTTTC CAGCCAGTGT GTTGGTAATA AA - #AGTCACCT        120                                                                          - TTCAGAGCTT TGGTCCCCGT AATGCCCGTC TTTCCTGTGT CCAGGAATAA CC - #TTTGNTAC        180                                                                          - TAGGCAGTCC TCTGAAAGAT TTGTAGAAGG TTAAAGTGGA AAGGGACTTG GA - #AGCTCATA        240                                                                          - GAATCCATGC CTCTTCTTTT AGCATCAAGG AATTAGAAGT CCTGAGAGAT GA - #AGAATGTT        300                                                                          - GTCTTCCCAA CTCAAACCCA TTTCTTGAAG CCATTTCCCT GGTTACTGNA TT - #GGCCACAA        360                                                                          - CCCTTCCCCC TTGNTATCCT CATCCTGCTA ATGCTGTTTT TAATGGCCTG CC - #AGTCTGGA        420                                                                          - TTTGTCTTTG GCAACCAAAC AATTTTGCTT CACAAGATTC CTACTTAAGG GA - #AGAGAGGG        480                                                                          - GCTCCTCATT TNTCACTTGT ACAAGAGCAG GGCTGGTCAG CTTTACACAG GT - #GTCAGATG        540                                                                          - AACCGTCACA ANCCAGANTT NCATGTTGGC CTCAGGAGGG CTTCNAGGTC CA - #ACATCTCG        600                                                                          - ACGTAAGGAG CGTTCCCAGT TCTTTCATGC TCAGATAACA GTNCTAACTN CA - #GCTGTTTC        660                                                                          - ATCCCNAATC CCTANTTGAG GTCTTAACAT CTATTCCATT TTKCCNACMA GG - #GTTATNCT        720                                                                          #                766GAN TTAGANCTGA CTGATNCACT TCCTAG                          - (2) INFORMATION FOR SEQ ID NO:39:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 327 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                                - TCATACTTGT ATAGTTCKNT AAGATAATCA CTCTCTCACT CAGACATNNG GN - #GRARNGCC         60                                                                          - CNTCGATCAC TTGGGANAGG NGACTTGCMA TGTTTAATGA TTGTCANCCM NA - #NAANTAAG        120                                                                          - CTNACAGGGC AAAAACAGCC TYANGTCAGT TCTNTCTCCC TAATCCTCTA GR - #AKNAAATC        180                                                                          - NNAWRNTRNN ACTCTGNNTC TGTGCCATNA NANATNTTNC ANTTGTATTT AT - #GNACTCCA        240                                                                          - CATNGAGTAC ACCTCACTAA WTNTNCTNCT GGGNAACNCC CSCMCCANTT TT - #TNNTTGNT        300                                                                          #            327   GGCA TACNGTG                                               - (2) INFORMATION FOR SEQ ID NO:40:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 431 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:                                - CCAGACTTTC ATAACTNGTG TTATTATGAA GATTAGAGTN CTGAAGCTTA CT - #GGATTAGA         60                                                                          - AGAGNACGAG GGGGTAGCTG CCCCAATATA TTCTAATTTC TCTKGAGGAC CA - #CCAAATNG        120                                                                          - GMAGAGTGTC TCTGATAGGG AAAAGGAAGA GTTGGAAGGN ATCTTAGCCT CT - #AGGANAAA        180                                                                          - AGAACCATTT TTATTGGCCA CCAAAGTTAC ATCTAGTKGC CTACAAATTT AT - #NTCCAAAC        240                                                                          - TCCTTATCCT GCCAATTCAG GGTCCTGNAA ACTGATGCCA AACTATAGTT TA - #GTCTNCTA        300                                                                          - TCACATGACT GCATTATACA TACCCAATTA TCTGGGMAAA CAGACCTGAT CC - #AAACACAG        360                                                                          - TTKGGTNCTT TCCTTNCCTT NCCTTKGTTT AGCCTGTYCC GTCTACTNGG GG - #TGTCTTKG        420                                                                          #      431                                                                    - (2) INFORMATION FOR SEQ ID NO:41:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 276 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                                - TTTTTTTCCA CCAGACTTAC CAAATTTTAG ATGNATGGAA GAACTGTAAA TN - #CCCATAAA         60                                                                          - GNTAATCTAT NCATNGACCC CCACCATTAT GATAGAGATC ATNTGGTGAN TA - #ATGAAAGA        120                                                                          - TGAAACTCTC AGCTGGGAAA GTAANAAGGA ATAGGATGTA AGTATGAGCT CC - #TGTTTTTT        180                                                                          - ATTATNTTTA TGGATGCCCC CTCAGAAAAA TATGNAANGG GGTAACTGAC TN - #GGAAATGG        240                                                                          #      276         AAGT CCCACTCACG AGGTTT                                     - (2) INFORMATION FOR SEQ ID NO:42:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 270 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                                - TCGAGATCTA AAGCAGATGN AGACTTTNCA CNAAATAAAT TTACTGCTTT TT - #TYCTGTGA         60                                                                          - NATAAGTTNC GAGAAGGAAA GCTTTKGATT NCTRNATGAG TYCAGTGGAT TA - #TYCTNAGN        120                                                                          - ACTAGAGTKG NKGTKGAAGN CATGGNACAT TTATATAGWT YWTTCAGTTC TA - #CACTAAAT        180                                                                          - GATGGAAGAA TGAGAAATCC TATATGACAA ATAGAAAAGT YCATYCTYCA TA - #ATTGAGAA        240                                                                          #          270     TACC AAGATCTCGA                                            - (2) INFORMATION FOR SEQ ID NO:43:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 580 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                                - CTTAGTTTTA GACTAGTTTC ATTATACTAC CAGTTTCTAA TATGTTGGTT TT - #TTATTCAC         60                                                                          - TATTTGATAT ATTTGTTTTA ATATATGTTC TTGTTTTAGC AGGTAAAAGA AT - #CATAACAA        120                                                                          - ATGTTTTTAA AAGAACATTA TTATTCTTTA ATAACTGTCT TTTTATGCAT TT - #GGCATGCC        180                                                                          - AACTTTTTTC ATTAACATCT TGGGTATTTT ATAAAAAGAG GGAAAGCTCA AT - #GTTTAACA        240                                                                          - GGTAGCTTTT CTTAGGAGCT AAATTAAATA TTTAACAAAT CTCCTTCCCT TC - #NCCCTTCC        300                                                                          - CCATCCCTCA AAGNATGGGT GNANTTATCT TTAACTTTTG GGCTNGCATC CN - #TGNAAGCT        360                                                                          - TATGGNTANT CATAGTCTNA CMAAACTAGG GTCACCNAAC TTGGCAGCAG AA - #ATAATCTA        420                                                                          - GTCTTACTGT GATAACTACC CAATTACTTT ATTATTTTTC CAGTTNCAGT TC - #CAAATGTT        480                                                                          - TTGTGGNAAN AATTTTTNCT GTTTGTGATT TTCCAAGCTT AGAGGGGGAA AC - #CAACTTTC        540                                                                          #   580            TGNA TAGTTTATGN ATTGTGTAAA                                 - (2) INFORMATION FOR SEQ ID NO:44:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 347 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                                - TGTTTCTTAA NACAGAAAAA AATTTACTGA TNGGACATTG TTCTAAGTGT AT - #TATTGTAT         60                                                                          - TAAATGGATC ATTTAATTTA ATCTTCATAA CTGACATAGG AGTTGAGTAA CT - #TGTGTGGT        120                                                                          - CAAATAGCTA GTAAGTGATG AGTAGGCTGG GCGCAGTGGC TCAAGCCTGT AA - #TCCCAGCA        180                                                                          - CTCTGGGAGG CTGAGGCAGG CAGATCACTT GAGGTCAGGA GTTTGAGACC AG - #CCTGGNCA        240                                                                          - ACATGGNAAA ACCTCGTCTC TACTAAAAAT ACAAAAATTA GCTGGGCGTG GT - #GGGNGCGC        300                                                                          #               347ACTC GGAAGGCTGA GGCAGGAGGA ATCGCTT                         - (2) INFORMATION FOR SEQ ID NO:45:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 430 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                                - GCTCATCATG CTTCACGGGG GAGGCTGTGC GGGAAGAATG CTCCCACACA GN - #ATAAAGAA         60                                                                          - TGCTCCCGCA CAGGATAGAG AATGCCCCCG CACAGCATAG AGAAGCCCCC GC - #ACAGCATA        120                                                                          - GAGAATGCCC CCNCACAGCA TAGAGAAGCC CCCGCACAGN ATAGAGAATG CT - #CTTCACCT        180                                                                          - CTGGGTTTTT AACCAGCCAA ACTAAAATCA CAGAGGGCAA CACATCATTT AA - #GATAGAAA        240                                                                          - TTTCTGTATC TTTTAATTTC TTTCAAAGTA GTTTTACTTA TTTNCAGATT CT - #ATTTCTTT        300                                                                          - ACTAGAATTA AGGGATAAAA TAACAATGTG TGCATAATGA ACCCTATGAA AC - #AAACAAAA        360                                                                          - GCTAGGTTTT NTNCATAGGT CTNCTTCCNN ATTGAATGAA CGTCTNTCCT CA - #AATTTANC        420                                                                          #       430                                                                   - (2) INFORMATION FOR SEQ ID NO:46:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 400 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                                - CAAACCCTAT GNGAAATGGA AAGGAAACTA TTCTAAAGCA TAAAAGGTAG AA - #ATATATAT         60                                                                          - ACCACCCATC AAGAAAGATT ATTTTTGNTG AACTCAAGTC ACCAGAGTGG CT - #AAAGCCCA        120                                                                          - GTAGAATGGA AATGATTATA TGGAAGGTGA GGCCAACGGG ACCAGAACAT AC - #TGTGATAG        180                                                                          - ACAGNAAGGA GCTGTCTATC TTCTATTCTC CCACAGAAGG AGGTGACTAA GT - #CANCTGCC        240                                                                          - CAAGCAATGT TATATCTGCA ATTGATGTNC AGCAGTACAA GTCTGAACAA CT - #TGGATTGG        300                                                                          - NTGATTAATG TCCACANTAA ACATACAAGT CNTAATAGCT ATCTCTATAT AG - #TCTTTGGG        360                                                                          #   400            NCAC ATNATCTCAC CTATTCCTCC                                 - (2) INFORMATION FOR SEQ ID NO:47:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 500 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                                - AGNATCCAGA ATTGAGTGNA GNGTTCTCTG GNCCACAGTC TCGGTATCTN CT - #GTGAAATG         60                                                                          - GGGTATAGAT TCTACAATAA AACAAACACA NNGGCCCTAG GTCAGTGTTA AT - #GGAGATCA        120                                                                          - CCANCCACAT TACCACCTCC AACACAGAAT TTTCTTTTTC TTAATNCAAT NC - #GTNTCTTA        180                                                                          - TAAGTCACTT TNCCCCAACT CACCAATCTA GNTAAGAATT TTTACCCTGA GA - #AAAACAGC        240                                                                          - TACACTCTAA AATTGCTNCA AAGAAAATGT CTAACATNTG GAAAGAAGGA CT - #TAACATGT        300                                                                          - GANGNAGACA CTGGCTCCAT CTAGNGGGTG CTTTNTTTTG AAATAATTAT AA - #TNCCNCAT        360                                                                          - CAAATTTTNG GGGGNTACAG CTTATTAGGA ACTTGTTATA GAACCAGATT CT - #GCCACAGA        420                                                                          - ANCCACGTGG GTTGACAAGT GGTTGNCAGA AGAAAGGTAA TATGGCTTAT NA - #TTAGGGNC        480                                                                          #500               ATTG                                                       - (2) INFORMATION FOR SEQ ID NO:48:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 460 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                                - AAAATGCTTG ANNCAAATGT CATCTAGTTC CATCTCTACG ACTCTCATGG GG - #TCCAAAGA         60                                                                          - AGAGTTTTAN TTGAGTTTTA GAATGTGAAG TTGTGAAGTG TCTGAAAAAC TA - #CATGGTGN        120                                                                          - TCTGAAAGNC AAACTTTTAG CCTTGGGGGA GAGCATCTAA GACAGNAGGT GA - #AGGGNAGG        180                                                                          - GGTTAGAACT AGAGGGATTG AAGAATATTA TCCATATAGG TTAGGGTTAG GT - #NNGGCAAC        240                                                                          - GTTTTATAGA ACAAACATTG GCAAGCTACA GCCACAGGCC AGATCTGTCT NC - #TACCTTCC        300                                                                          - CACAAAGGTG TAATAACAAA GTTATTCACA AATGTGTGAA TAAACTNNCA TT - #GGAAAGTG        360                                                                          - CCCACGCTCC TNGGTTTATA CATTGTCTGT GGCTGCTTTC ACACTACAGT AG - #CACAGGTG        420                                                                          #   460            ACCA TATGCCCCAT AGAGCTTTAA                                 - (2) INFORMATION FOR SEQ ID NO:49:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 370 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                                - ATCAAGCAAC AGTGTGTTAT GCCTATACTC CATGTTTATA TGTGTGTATT AA - #AAAATGTA         60                                                                          - TTTGTATATA TGTGTATGTA TAAGTGTGTG TGTGTGTATG ATGATTCTNC TC - #CCGNTTTG        120                                                                          - AAGGTGAAAG AAAGCACACC TTTATTTAAG CATAAACTTT GGGTTTCAGA TA - #CTGTCTGG        180                                                                          - AAAAATGATT TATCTCCCAC TTTGAAATTC CAAAATACGT ACATATATTT TT - #TTTTTCTT        240                                                                          - TTCTTTTTTA GTTTNAGGGT CTTGCTGTGT TGCCCAGGCT GGAGTGCAGT AG - #TGTGATCA        300                                                                          - TAGNTCACAC AGNCTCTAAC TCCCAGGNTC AAGNTATCTT CCTGCCCCAG NC - #TCCTGAGT        360                                                                          #       370                                                                   - (2) INFORMATION FOR SEQ ID NO:50:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 500 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:                                - CAAAAAATCA AAGGGAAGNT GGAACCCCTG CCCACCTCTC CATTCCCCAT TC - #TGCTGGTG         60                                                                          - GTGNCTGCTC TTCCTCACAG TACCTCCTGA AAAGTTCAGA ATTCAGTTAA TA - #CAGAATTA        120                                                                          - TTGGGTTGAT TTTCAACGTG TAGTTTAAGA TGAAGAGTTC CGNTTGGTTT AA - #ACCACTTC        180                                                                          - ACCTAACCTC TTGGTAACGG TAGTCCTGAG AGTTCGCAGT GTCANTGAAA AT - #CGTCCTGT        240                                                                          - GACCACGCGT CAAGCTGCTG ATGGGGGACA GAAACTTCCG GGNCTATCAT AT - #CTCCTTGA        300                                                                          - NCTCGGCCCT CAAATCTGGT AGTTTCTGCA CCGAGGGACA CAGTCCACTG CG - #ATGAAGTA        360                                                                          - TGTTCAAAAT CGNTTTCTTT AGGGAACTCC TTCCAAAGTC CAATAGTGNA AG - #GTGGTCAA        420                                                                          - GGAAGGATTT GGAAGGAAGN TGNAAAAGTC AGNCGGGAAT CTTGATTTGG NT - #AGNTGTGG        480                                                                          #500               GGCC                                                       - (2) INFORMATION FOR SEQ ID NO:51:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 105 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:                                - GGAAAGAGGT CTCCTAACAC CCAGACAGTG TAAAAATCCA GTTTTTCTTC CT - #TTTGGNNG         60                                                                          #                 105GT AGCTCAGGCT GGAGTGCAGT GGCAC                           - (2) INFORMATION FOR SEQ ID NO:52:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 386 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:                                - AGTCCCAGCT ACTCAGGAGG CTGGGGCAGG AAGATAGCTT GAGCCTGGGA GT - #TAGAGGCT         60                                                                          - GTGTGAGCTA TGATCACACT ACTGCACTCC AGCCTGGGCA ACACAGCAAG AC - #CCTAAAAC        120                                                                          - TAAAAAAGAA AAGAAAAAAA AAATATATGT ACGTATTTTG GAATTTCAAA GT - #GGGAGATA        180                                                                          - AATCATTTTT CCAGACAGTA TCTGAAACCC AAAGTTTATG CTTAAATAAA GG - #TGTGCTTT        240                                                                          - CTTTCACCTT CAAAGCGGGA GAAGAATCAT CATACACACA CACACACTTA TA - #CATACACA        300                                                                          - TATATACAAA ATACATTTTT TAATACACAC ATATAAACAT GGAGTATAGG CA - #TAACACAC        360                                                                          #             386  ATAG GGATCC                                                - (2) INFORMATION FOR SEQ ID NO:53:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 377 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:                                - TATATTTNAT CAAGCAACAG TGTGTTATGC CTATACTCCA TGTTTATATG TG - #TGTATTAA         60                                                                          - AAAATGTATT TGTATATATG TGTATGTATA AGTGTGTGTG TGTGTATGAT GA - #TTCTCCTC        120                                                                          - CCGNTTGAAG GTGAAAGAAA GCACACCTTT ATTTAAGCAT AAACTTTGGG TT - #TCAGATAC        180                                                                          - TGTCTGGAAA AATGATTTAT CTCCCACTTT GAAATTCCAA AATACGTACA TA - #TATTTTTT        240                                                                          - TTTTCTTTTC TTTTTTAGTT TNAGGGTCTT GCTGTGTTGC CCAGGCTGGA GT - #GCAGTAGT        300                                                                          - GTGATCATAG NTCACACAGG CTCTAACTCC CAGGNTCAAG CTATCTTCCT GC - #CCCAGNCT        360                                                                          #  377             T                                                          - (2) INFORMATION FOR SEQ ID NO:54:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 521 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:                                - CTGCAGTAAG CCACGTTCAT GCCACTGTAC TCTAGCGTGG ATGACAGAGA GA - #GATCCTGT         60                                                                          - CTTTGGAAGA AAAAAACAAA AAGAAAAAAA AAAGAGTATG GCCATGGCCT TA - #TAATATAG        120                                                                          - AAGGGGTCAC ATATTAATCT CTGAAAATGG ATCTCTTGTG GGCTTTCATA CA - #AGGCAACA        180                                                                          - GCCACAGAGT ACGTACCTGA AAGCTGCCTG GGNTTAATGG CTGGNAGTAT GT - #TCTAACTN        240                                                                          - GTTCAGGNAC CCATGTCACN ACTGGTGGTT ACAGAATGTG AATCTCACAC TG - #TCCNAAAT        300                                                                          - CGGTTTTATT TTTAAAANGA ATAATTCTAN TACATTACCT TATAAAAAGT AG - #GTAACCTA        360                                                                          - ATTTTGGNTT TTAAAAGTGA ATTGAGGGCA GATGCAAGTG GNTCACACCT AT - #TAATCCCA        420                                                                          - AATACCTTGG AGAGGGCAAG GTAGGAGGAT TGGTTGGAGC CCAGGAGTCC AA - #AGACCAGG        480                                                                          #  521             GAAN GTCCTCTCTA CAANAAANAA T                               - (2) INFORMATION FOR SEQ ID NO:55:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 516 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:                                - CTGCANGAAG CTTTTNTTNC TTTTNGGNGG AGACAGAGTC TTGCTGTGTC AN - #CCCAGGCT         60                                                                          - GGGGTGCAGT GGNACAGTCA TAGCTCACTG CAACCTTGAA CTCCCTGGNT CA - #TGCGATCC        120                                                                          - TCCCACTTCA GCCTCTCAAG TAGCTAGAAC TACAGGTGTG CACCACCATG CC - #TGACTAAC        180                                                                          - TTGTTTATTN GNGGGAGAGA GAACGNTCTT GCTATATTGC CTAGGCTGGT CN - #TTGAACTC        240                                                                          - TTGGGNTNCA AGCAATCCTC CTACCTTGGC CTCTNCAAGG TANTTGGGAT TN - #ATAGGTGT        300                                                                          - GAGCCACNTG CATCTGGCCT CAATTCACTT TTAAAATNCA AAATTAGGTT AC - #CTACTTTT        360                                                                          - TATAAGGTAA TGTATTAGAA TTATTCTTNN NAAAAATAAA ACCGATTTGG GA - #AAGNGTGA        420                                                                          - GANTCACATT CTGTAACCAC CAGTGGTGAA ATGGGTCCCC GAACAAGGTA GA - #ACATACTC        480                                                                          #      516         GGGA GNGTTCAAGT CCGTNC                                     - (2) INFORMATION FOR SEQ ID NO:56:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 505 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:                                - GGATCCTGTT TCTTAAAACA GAAAAAAATT TACTGATAGN ACATTGTTCT AA - #GTGTATTA         60                                                                          - TTGTATTAAA TGGATCATTT AATTTAATCT TCATAACTGA CATAGGAGTT GA - #GTAACTTG        120                                                                          - TGTGGTCAAA TAGCTAGTAA GTGATGAGTA GGCTGGGCGC AGTGGNTCAA GC - #CTGTAATC        180                                                                          - CCAGCACTCT GGGAGGCTGA GGCAGGCAGA TCACTTGAGG TCAGGAGTTT GA - #GACCAGCC        240                                                                          - TGGCCAACAT GGNAAAACCT CGTCTCTACT AAAAATACAA AAATTAGCTG GG - #CGTGGTGG        300                                                                          - GTGCGCACTT GTAGTCCCAG CTACTCGGAA GGGTTGAGGC AGGAGGAATC GC - #TTGGTCCC        360                                                                          - CGGGAGGGAG AGGTTGNTNG TGNAGCTGAG ATCACGCCAC TNGCACTCCA GG - #CTGGGNAA        420                                                                          - CAAAAGGGAG ACCTTTNCTC AAAAAAAAAT NAAAATAAAA AGTGATGAGT AG - #GATTGGGA        480                                                                          #              505 TCCA AGACC                                                 - (2) INFORMATION FOR SEQ ID NO:57:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 500 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:                                - CTGCAGNCTC AAACCCTTGT CCTGGGATCA AACAATCCTC CCACCTCAGC CT - #TCAAAGTA         60                                                                          - GATAGAACTA CAGGCATGCA CTACCATGCC TAATTTTTTA AAAAAAAATT TT - #TTTTCAGA        120                                                                          - GATGAGATCT CACTGTGTTT CCCAGGNTTG TCCGGAACTC CTGGACTCAA GC - #GATCCTCC        180                                                                          - CACCTTGGGC TGCCAAAGTG TTGGGATTAC AGGCATGAGC CACCATGCCT GG - #CCATACAC        240                                                                          - TTTTTTTTTT TTTTTAANCA AGACGGAGTC TNGTTCTGTC GCCCAGACTG GA - #GTGCAGGG        300                                                                          - GCGTNNATCT TGGCTCACTT GAAAGCTTCG CCTCCCAGGG TTCATGCCGT TC - #TCCTGNCT        360                                                                          - CAGCCTCCCA AGTNGGTGGG ACTACAGGNA TCTGCACCAC GNCCGGTTAT TT - #NTTGGGTT        420                                                                          - TGNNGNAGGG ACGGGGTTTC ACCATGTTAG GCAGGATGAC TTCGGACTTC CN - #GACCCAAG        480                                                                          #500               CCCA                                                       - (2) INFORMATION FOR SEQ ID NO:58:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 440 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:                                - GAATTCCAGA CGAGCCTGGG CAACACAGTG AGACTCTATC ACTACAAAAA AA - #TTTTAAAA         60                                                                          - TTAGCTAAAG TTGATGGNAC ATGCCTGCAG TCCCAGCTAC TCAGGAGGCT GG - #GGCAGGAA        120                                                                          - GATAGCTTGA GCCTGGGAGT TAGAGGCTGT GTGAGCTATG ATCACACTAC TG - #CACTCCAG        180                                                                          - CCTGGGCAAC ACAGCAAGAC CCTAAAACTA AAAAAGAAAA GAAAAAAAAA AT - #ATATGTAC        240                                                                          - GTNTTTGGGG AATTTCAAAG TGGGAGATAA ATCATTTTTC CAGACAGTNT CT - #TGAAACCC        300                                                                          - AAAGTTTATG CTTAAATAAA GGTGTGCTTT CTTTCACCTT CAAANGCGGG AG - #AAGGATCA        360                                                                          - TCATNCACAC ACACACACTN ATCATNCACA TTTTTACAAA TNCAATTNNN NA - #ATACAACA        420                                                                          #440               TTTG                                                       - (2) INFORMATION FOR SEQ ID NO:59:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 513 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:                                - GGATCCTGTT TCTTAAAACA GAAAAAAATT TACTGATAGN ACATTGTTCT AA - #GTGTATTA         60                                                                          - TTGTATTAAA TGGATCATTT AATTTAATCT TCATAACTGA CATAGGAGTT GA - #GTAACTTG        120                                                                          - TGTGGTCAAA TAGCTAGTAA GTGATGAGTA GGCTGGGCGC AGTGGCTCAA GC - #CTGTAATC        180                                                                          - CCAGCACTCT GGGAGGCTGA GGCAGGCAGA TCACTTGAGG TCAGGAGTTT GA - #GACCAGCC        240                                                                          - TGGCCAACAT GGNAAAACCT CGTCTCTACT AAAAATACAA AAATTAGCTG GG - #CGTGGTGG        300                                                                          - NTGCGCACTT GTAGTCCCAG CTACTCGGAA GGCTNGAGGC AGGAGGAATC GC - #TTGATCCC        360                                                                          - NGGGAGGGAG AGGTTGGTNG TGANGCTGAG ATCACGNCAC TTGNACTCCA GN - #CTGGGNAA        420                                                                          - CAAANGNGAG ATCTTNTCTC AAAAAAAAAT AAAANTAAAA NGTGATGAGT AG - #GATTTGGA        480                                                                          #        513       TCCA GGACCTGGNA TTC                                        - (2) INFORMATION FOR SEQ ID NO:60:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 390 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:                                - GAATTCCTGG NCTCAAGTGA TCCTCTCACC TCAGCCTCCC AAATTGCTGG GA - #TTAGAGTG         60                                                                          - TGAGCCACTG TGCCTAGCCT GCATATATCT ATTTTTAATG ACTGCTAAAT CT - #CATTGTAT        120                                                                          - GAAAATTTAT GTCCTAGCTA TAAAATTTGN TAGCACATGT TTAATTTTTT CT - #AATTTCAG        180                                                                          - ATGTTTTAAA CTAATATTTC CCAAAGTATA GTATGGCATT TTAGGTATGA TA - #TGATCTTT        240                                                                          - NNTCCTCTTC GTACTCATTT TTATAGTTAT GGCCTGTGCA ACTGGTTTCC CA - #TTTATATG        300                                                                          - AATGATACAG AGCTTCCTAT TAAGAAAAAG TTCAGCTTGG GGAAAAAAAA AG - #TGAATTGT        360                                                                          #          390     AAGT GAATTATTGG                                            - (2) INFORMATION FOR SEQ ID NO:61:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 366 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:                                - TCAAGTACCT CCCTGAATGG ACTGCGTGGC TCATCTTGGC TGTGATTTCA GT - #ATATGGTA         60                                                                          - AAACCCAAGA CTGATAATTT GTTTGTCACA GGAATGCCCC ACTGGAGTGT TT - #TCTTTCCT        120                                                                          - CATCTCTTTA TCTTGATTTA GAGAAAATGG TAACGTGTAC ATCCCATAAC TC - #TTCAGTAA        180                                                                          - ATCATTAATT AGCTATAGTA ACTTTTTCAT TTGAAGATTT CGGCTGGGCA TG - #GTAGCTCA        240                                                                          - TGCCTGTAAT CTTAGCACTT TGGGAGGCTG AGGCGGGCAG ATCACCTAAG CC - #CAGAGTTC        300                                                                          - AAGACCAGCC TGGGCAACAT GGCAAAACCT CGTATCTACA GAAAATACAA AA - #ATTNGNCG        360                                                                          #          366                                                                - (2) INFORMATION FOR SEQ ID NO:62:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 498 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:                                - AACACCAGGG NCATGAGGGC ACTAATCATA ATGAGATATG CCTGCTGGAG TC - #GAAGTGGA         60                                                                          - CCTTTCCAGT GAATGGAAAT CATTCCCACC ACACCAAAAT TCCAGATCAG GA - #GTGNAACA        120                                                                          - GTAATGTAGT CCACAGCAAC GTTATAGGTT TTAAACACTT CCCTGAAAAA AA - #ATTACACA        180                                                                          - GATTTTAAAA GATGTACAAT AATTTCCACC AAAACATTAT TTAGAATAAT GT - #GATGGCTC        240                                                                          - CCAAACATTA GATATTAATN TCCCACCTTT ATAATTTTAC CATAACCTAT AT - #CAACTGTG        300                                                                          - CTATTATTTA TTTAATNCTT CCCTNTAAAT TAATTTACTC TTTTTTTGTT TT - #TGTTTTTG        360                                                                          - NGTTTGGAGC CAGTGTCTCA TTTTGGTTGC CCAGGCTTGG AGTAAAGTGG GT - #GCAATCAC        420                                                                          - GGCTCAACTG NAGTCTTTNC CTCCNGGAGA TCAGGTNGGT CTTCCCCAGG TC - #CAANCTCC        480                                                                          # 498              AC                                                         - (2) INFORMATION FOR SEQ ID NO:63:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 469 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:                                - TAAACAACAG GGNCATGAGG GCACTAATCA TAATGAGATA TGCCTGCTGG AG - #TCGAAGTG         60                                                                          - GACCTTTCCA GTGAATGGAA ATCATTCCCA CCACACCAAA ATTCCAGATC AG - #GAGTGAAA        120                                                                          - CAGTAATGTA GTCCACAGCA ACGTTATAGG TTTTAAACAC TTCCCTGAAA AA - #AAATTACA        180                                                                          - CAGATTTTAA AAGATGTACA ATAATTTCCA CCAAAACATT ATTTAGAATA AT - #GTGATGGC        240                                                                          - TCCCAAACAT TAGATATTAA TNTCCCACCT TTATAATTTT ACCATAACCT AT - #ATCAACTG        300                                                                          - TGCTATTATT TATTTAATNC TTCCCTCTAA ATTAATTTAC TCTTTTTTTG TT - #TTTGTTTT        360                                                                          - TGTGTTTGGA GCCAGTGTCT CATTTTGGTT GCCCAGGCTT GGAGTAAAGT GG - #GTGCAATC        420                                                                          #              469TCTTT ACCTCCCGGA GATCANGTTG GTCTTTCCC                       - (2) INFORMATION FOR SEQ ID NO:64:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 370 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:                                - GTTTATCAAG TACCTCCCTG AATGGACTGN GTGGCTCATC TTGGCTGTGA TT - #TCAGTATA         60                                                                          - TGGTAAAACC CAAGACTGAT AATTTGTTTG TCACAGGAAT GCCCCACTGG AG - #TGTTTTCT        120                                                                          - TTCCTCATCT CTTTATCTTG ATTTAGAGAA AATGGTAACG TGTACATCCC AT - #AACTCTTC        180                                                                          - AGTAAATCAT TAATTAGCTA TAGTAACTTT TTCATTTGAA GATTTCGGCT GG - #GCATGGTA        240                                                                          - GCTCATGCCT GTAATCTTAG CACTTTGGGA GGCTGAGGCG GGCAGATCAC CT - #AAGCCCAG        300                                                                          - AGTTCAAGAC CAGCCTGGGC AACATGGCAA AACCTCGTAT CTACAGAAAA TA - #CAAAAATT        360                                                                          #       370                                                                   - (2) INFORMATION FOR SEQ ID NO:65:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 316 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:                                - GTCATGGTGT TGGCGGGGAG TGTCTTTTAG CATGCTAATG TATTATAATT AG - #CGTATAGT         60                                                                          - GAGCAGTGAG GATAACCAGA GGTCACTCTC CTCACCATCT TGGTTTTGGT GG - #GTTTTGGC        120                                                                          - CAGCTTCTTT ATTGCAACCA GTTTTATCAG CAAGATCTTT ATGAGCTGTA TC - #TTGTGCTG        180                                                                          - ACTTCCTATC TCATCCCGNA ACTAAGAGTA CCTAACCTCC TGNAAATTGA AG - #NCCAGNAG        240                                                                          - GTCTTGGCCT TATTTNACCC AGCCCCTATT CAAAATAGAG TNGTTCTTGG NC - #CAAACGCC        300                                                                          #   316                                                                       - (2) INFORMATION FOR SEQ ID NO:66:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 448 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:                                - CTGCAGNCCG GGGGATCCTG GTAAAAGTCA CAAGGTCAGC CTACTAAAGC AG - #GGAAAACT         60                                                                          - AAAGGCAAGT AAACACGTGC AGACAAAAAA AGGGATAAAG AAAAGGAATT AA - #GAAACTAG        120                                                                          - CATTTTTAAN GTGGGGGAGG TGAATGCTTC CCAGAATGGG TTTATATCAC TT - #GCTTGNGG        180                                                                          - GCCTTCTGAG TGTTGGNAAC AACCTGTCAT CATCACACAT ACCTGTCATC TT - #TAATGGTC        240                                                                          - TCCATACATT ACTAATAGAT TATACAGATG GCCATCACTT AACACTTCCA CT - #CACTCAAT        300                                                                          - TTGTNCAACA TGCAAGGTTA CCCTCTTTTT TNGCTTACNG CCACAAAGCA TT - #GGANAAGG        360                                                                          - TTTGTGATTT TTACTAGCCN CCACTTCATC AAATTTAAGC ATTTTCTTTT TC - #CTNTTAAC        420                                                                          #            448   AACN AAGGAAAT                                              - (2) INFORMATION FOR SEQ ID NO:67:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 450 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67:                                - CTGCAGCTCC AAGCACCTTT TTCAAATTCA GCTTTCTGTG ATTTCAGACC AC - #ATATGCAA         60                                                                          - GGAACTATCT TACCTTAATT AATAAGACTT TAAAATCCTT GTGTCAGAGG CG - #TTTGGACC        120                                                                          - AGAGCAACTC TATCTTGAAT AGGGGCTGGG TAAAATAAGG CCAAGACCTA CT - #GGGCTGCA        180                                                                          - TTTGCAGGAG GTTAGGTACT CTTAGTTACG GGATGAGATA GGAAGTCAGC AC - #AAGATACA        240                                                                          - GCTCATAAAG GATCTTGCTG ATAAAACTGG TTGCAATAAA GAAGCTGGNC AA - #AACCCACC        300                                                                          - AAAACCAAGA TGGTGAGGAG AGTGACCTCT GGTTATCCTC ACTGNTCACT AT - #ACGNTAAT        360                                                                          - TATTATACAT TAGCATGCTA AAAGACACTC CCCGCAACAA CCATGANAGG TT - #TACAAGTT        420                                                                          #          450     CGGA NGNTANCTTG                                            - (2) INFORMATION FOR SEQ ID NO:68:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 388 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:                                - CTGNAGCCTC CACCACCCAG GTTCAGGTGA TTCTCCTGCC GTAGNCTCAT GA - #GTAGNTGG         60                                                                          - GATTACAGGC ATGTGCCACC ATGCCCGACT AATTTTTATA TTTTTAGTAG AG - #ACGGGGTT        120                                                                          - TCACCATGTT GGGCAGGCTG GTCTCAAACT CCTGACCTCA AGTGATCTGC CC - #ACCTTGGC        180                                                                          - CTCCCAAAGT GCTGGGATTT CAGGCGCCTG GCCTGTTACT TGATTATATG CT - #AAACAAGG        240                                                                          - GGTGGATTAT TCATGAGTTT TCTGGGAAAG AGGTGGGCAA TTCCCGGAAC TG - #AGGGATCC        300                                                                          - CTCCCCTTNN NAGACCATAC AAGGTAACTT CCGGACGTTG GCATGGNATC TT - #GTTAAACT        360                                                                          #            388   GGGA GTGTCTTT                                              - (2) INFORMATION FOR SEQ ID NO:69:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 500 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:                                - CTGCAGAAGT ATGTTTCCTG TATGGTATTA CTGGATAGGG CTGAAGTTAT GC - #TGAATTGA         60                                                                          - ACACATAAAT TCTTTTCCAC CTCAGGGNCA TTGGGCGCCC ATTGCTCTTC TG - #CCTAGAAT        120                                                                          - ATTCTTTCCT TTTCTAACTT TGGTGGATTA AATTCCTGTC ATCCCCCTCC TC - #TTGGTGTT        180                                                                          - ATATATAAAG TNTTGGTGCC GCAAAAGAAG TAGCACTCGA ATATAAAATT TT - #CCTTTTAA        240                                                                          - TTCTCAGCAA GGNAAGTTAC TTCTATATAG AAGGGTGCAC CCNTACAGAT GG - #AACAATGG        300                                                                          - CAAGCGCACA TTTGGGACAA GGGAGGGGAA AGGGTTCTTA TCCCTGACAC AC - #GTGGTCCC        360                                                                          - NGCTGNTGTG TNCTNCCCCC ACTGANTAGG GTTAGACTGG ACAGGCTTAA AC - #TAATTCCA        420                                                                          - ATTGGNTAAT TTAAAGAGAA TNATGGGGTG AATGCTTTGG GAGGAGTCAA GG - #AAGAGNAG        480                                                                          #500               ATGA                                                       - (2) INFORMATION FOR SEQ ID NO:70:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 435 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:                                - CTGCAGAGTA ATTGCAACTG GAGTTGTCTT AAGATAATGT CACATATCCA TC - #TTCCCCTT         60                                                                          - GTTTCTCATT CACAGAAAAA CATTTTTATT CCAGGTGCCA ATATTCCCAG CC - #AAAAAGAC        120                                                                          - TTTACTTCTG ACTCCCTTAT ATTTAGGATG GCTATGAGAA CAAGTAAGGG CA - #ATGACTTC        180                                                                          - TAGGGAGATG TGTTGTGTAT GGAACTTCTA AGGAGAGAAT TCTGCTGACA TG - #TCCTATGT        240                                                                          - TCTTTTCTCC CCTACTCCTT CCTACTGTCA GAAATGAAGG CTAGGGCTCC AG - #CCTGGACC        300                                                                          - CTGAAGTAAG CTAGAGGTTA GAAGCTAAAG AAGAAAGAAG GAGATTGAGT CC - #TTGGATGA        360                                                                          - ACGTGAAGCC ACCCTACTAA TCTGGACTGN CTACCTCTGN ACTACTCTAT GA - #GAGAGAAA        420                                                                          #   435                                                                       - (2) INFORMATION FOR SEQ ID NO:71:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 439 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:                                - CATGCTCTTT GTCCCTGTGA CTCTCTGCAT GGTGGTGGTC GTGGNTACCA TT - #AAGTCAGT         60                                                                          - CAGCTTTTAT ACCCGGAAGG ATGGGCAGCT GTACGTATGA GTTTGGTTTT AT - #TATTCTCA        120                                                                          - AAGCCAGTGT GGCTTTTCTT TACAGCATGT CATCATCACC TTGAAGGCCT CT - #GCATTGAA        180                                                                          - GGGGCATGAC TTAGCTGGAG AGCCCATCCT CTGTGATGGT CAGGAGCAGT TG - #AGAGAGCG        240                                                                          - AGGGGTTATT ACTTCATGTT TTAAGTGGAG AAAAGGAACA CTGCAGAAGT AT - #GTTTCCTG        300                                                                          - TATGGTATTA CTGGATAGGG CTGAAGTTAT GCTGAATTGA ACACATAAAT TC - #TTTTCCAC        360                                                                          - CTCAGGGGCA TTGGGCGCCC ATTGNTCTTC TGCCTAGAAT ATTCTTTCCT TT - #NCTNACTT        420                                                                          #439               TGT                                                        - (2) INFORMATION FOR SEQ ID NO:72:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 318 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:                                - TCCATCTCTA CGACTCTCAT GGGGTCCAAA GAAGAGTTTT AATTGAGTTT TA - #GAATGTGN         60                                                                          - AGTTGTGAAG TGTCTGAAAA ACTACATGGT GNTCTGAAAG NCAAACTTTT AG - #CCTTGGGG        120                                                                          - GAGAGCATCT AAGACAGNAG GTGAAGGGGA GGGGTTAGAN CTAGAGGGAT TG - #AAGAATAT        180                                                                          - TATCCATATA GGTTAGGGTT AGGTGTGGCA ACGTTTTATA GAACAAACAT TG - #GNAAGCTA        240                                                                          - CAGACACAGG CCAGNTCTGT CTNCTACCTN TCCACAAAGG TGTNATAACA AA - #GTTANNCA        300                                                                          # 318              CT                                                         - (2) INFORMATION FOR SEQ ID NO:73:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 450 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:                                - GTTGCAAAGT CATGGATTCC TTTAGGTAGC TACATTATCA ACCTTTTTGA GA - #ATAAAATG         60                                                                          - AATTGAGAGT GTTACAGTCT AATTCTATAT CACATGTAAC TTTTATTTGG AT - #ATATCAGT        120                                                                          - AATAGTGCTT TTTCNTTTTT TTTTTTTNTT TTTTTTNNTT TTNGGGGANA GA - #GTCTCGCT        180                                                                          - CTGTCGCCAG GTTGGAGTGC AATGGTGCGA TCTTGGCTCA CTGAAAGCTC CA - #CCNCCCGG        240                                                                          - GTTCAAGTGA TTCTCCTGCC TCAGCCNCCC AAGTAGNTGG GACTACAGGG GT - #GCGCCACC        300                                                                          - ACGCCTGGGA TAATTTTGGG NTTTTTAGTA GAGATGGCGT TTCACCANCT TG - #GNGCAGGC        360                                                                          - TGGTCTTGGA ACTCCTGANA TCATGATCTG CCTGCCTTAG CCTCCCCAAA GT - #GCTGGGAT        420                                                                          #          450     TGTT CCTGGGCCTC                                            - (2) INFORMATION FOR SEQ ID NO:74:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 489 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:                                - CTGCAGNTGA GCCGTGATTG CANCCACTTT ACTCCNAGCC TGGGCAANCA AA - #ATGAGACA         60                                                                          - CTGGCTNCAA ACACAAAAAC AAAAACAAAA AAAGAGTAAA TTAATTTAAA GG - #GAAGTATT        120                                                                          - AAATAAATAA TAGCACAGTT GATATAGGTT ATGGTAAAAT TATAAAGGTG GG - #ATATTAAT        180                                                                          - ATCTAATGTT TGGGAGCCAT CACATTATTC TAAATAATGT TTTGGTGGAA AT - #TATTGTAC        240                                                                          - ATCTTTTAAA ATCTGTGTAA TTTTTTTTCA GGGAAGTGTT TAAAACCTAT AA - #CGTTGCTG        300                                                                          - TGGACTACAT TACTGTTGCA CTCCTGATCT GGAATTTTGG TGTGGTGGGA AT - #GATTTCCA        360                                                                          - TTCACTGGAA AGGTCCACTT CGACTCCAGC AGGCATATCT CATTATGATT AG - #TGCCCTCA        420                                                                          - TGGCCCTGGT GTTTATCAAG TACCNCCCTG AATGGACTGG GTGGCTCATC TT - #GGCTGTGA        480                                                                          #        489                                                                  - (2) INFORMATION FOR SEQ ID NO:75:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 449 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:                                - CTGCAGNCTT GACCTCCTGG GATCAATCGA TCCTCCCACC TCAGCCTCCT AA - #GTAGCTGG         60                                                                          - AACTACAGGT GTGCACCACC ATGCCCGGCT AATTTTTGTA TTTTCTGTAG AT - #ACGAGGTT        120                                                                          - TTGCCATGTT GCCCAGGCTG GTCTTGAACT CTGGGCTTAG GTGATCTGCC CG - #CCTCAGCC        180                                                                          - TCCCAAAGTG CTAAGATTAC AGGCATGAGC TACCATGCCC AGCCGAAATC TT - #CAAATGAA        240                                                                          - AAAGTTACTA TAGCTAATTA ATGATTTACT GAAGAGTTAT GGGATGTACA CG - #TTACCATT        300                                                                          - TTCTCTAAAT CAAGATAAAG AGATGAGGAA AGAAAACACT CCAGTGGGGC AT - #TCCTGTGA        360                                                                          - CAAACAAATT ATCAGTCTTG GGTTTTACNA TATACTGAAA TCACAGCCAA GA - #TGAGCCAC        420                                                                          #           449    GGTA CTTGATAAA                                             - (2) INFORMATION FOR SEQ ID NO:76:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 490 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:                                - TTCTTGCCGT TCCCGACCCG AGCCTGGTGC CCCTTCCCCA TTATGATCCT TN - #TCGCTTCC         60                                                                          - GGCGGCATCG GGATGCCCCG CGTTGCAGGC CATNCTGTCC CAGNCAGGTA GA - #TGACGACC        120                                                                          - ATCAGGGACA GCTTCAAGGA TCGCTCGCGG CTCTTACCAG CCTAACTTCG AT - #CATTGGAC        180                                                                          - CGCTGATCGT CACGGCGATT TATCCCGCCT CGGCGAGCAC ATGGAACGGG TT - #GGCATGGA        240                                                                          - TTGTAGGCGC CGCCCTATAC CTTGTCTGCC TCCCCCGCGT TGCGTCGCGG TG - #CATGGAGC        300                                                                          - CGGNCCACCT CGACCTGAAT GGAANCCGGC GGCACCTCGC TAACGGATTC AC - #CACTCCAA        360                                                                          - GAATTGGAGC CAATCAATTC TTGCGGAGAA CTGTGAATGC NCAAACCAAC CC - #TTGGCAGA        420                                                                          - ACATATCCAT CGCGTCCGCC ATCTCCANCA GCCGCACGCG GCGCATCTCG GG - #CAGCGTTG        480                                                                          #       490                                                                   - (2) INFORMATION FOR SEQ ID NO:77:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 470 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:                                - CTGCAGTGTT TAAAAAATAA AATAAACTAA AAGTTTATTT ATGAGGAGTA CA - #CTGCTTTC         60                                                                          - TTGTAAACAC ATGTACAAGC CATATAATAG AGTTCATTTC NNACCCTAGT TA - #CGGAAACA        120                                                                          - CTAGAAAGTC TNCACCCGGC CAAGATAACA CATCTTTAGG TAAAAATAGC AA - #GAAATATT        180                                                                          - TTATGGGTTG TTTACTTAAA TCATAGTTTT CAGGTTGGGC ACAGTGGNTC AT - #GCCTGTAA        240                                                                          - TCCCAGCACT TTATGCGGCT GAGGCAGGCA GATCAGTTGA GGTCAGAAGT TT - #GAGACCAG        300                                                                          - CCTGGGCAAT GTGGCAAAAC CTCATCTCCA CTAAAAATAC AAAAATTAGC CA - #GGCATGGT        360                                                                          - GGTGCACACA TGTTAATTCC CAGCTACTTG GGAGGNTTGA GACAGGAGGG TC - #GCTTGGNC        420                                                                          #             470GTTGNA GGGANCTTAA TGTCACTGCA CTCTAGNTTG                      - (2) INFORMATION FOR SEQ ID NO:78:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 445 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:                                - CACTCAATTC TGAATGCTGC CATCATGATC AGTGTCATTG TTGTCATGAC TA - #NNCTCCTG         60                                                                          - GTGGTTCTGT ATAAATACAG GTGCTATAAG GTGAGCATGA GACACAGATC TT - #TGNTTTCC        120                                                                          - ACCCTGTTCT TCTTATGGTT GGGTATTCTT GTCACAGTAA CTTAACTGAT CT - #AGGAAAGA        180                                                                          - AAAAATGTTT TGTCTTCTAG AGATAAGTTA ATTTTTAGTT TTCTTCCTCC TC - #ACTGTGGA        240                                                                          - ACATTCAAAA AATACAAAAA GGAAGCCAGG TGCATGTGTA ATGCCAGGCT CA - #GAGGCTGA        300                                                                          - GGCAGGAGGA TCGCTTGGGC CCAGGAGTTC ACAAGCAGCT TGGGCAACGT AG - #CAAGACCC        360                                                                          - TGCCTCTATT AAAGAAAACA AAAAACAAAT ATTGGAAGTA TTTTATATGC AT - #GGAATCTA        420                                                                          #              445 TAGT GTAAA                                                 - (2) INFORMATION FOR SEQ ID NO:79:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 496 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:                                - CCTGTATTTA TACTGAACCA CCAGGAGGAT AGTCATGACT ACAATGACNC TG - #ATCATGAT         60                                                                          - GGCAGCATTC AGAATTGAGT GCAGGGCTCT CTGGCCCACA GTCTCGGTAT CT - #TCTGTGAA        120                                                                          - TGGGGTATAG ATTCTACAAT AAAACAAACA CAAAAGCCCT AGGTCAGTGT TA - #ATGGAGAT        180                                                                          - CACCAACCAC ATTACCACCT CCAACACAGA ATTTTCTTTT TCTTAATTCA AT - #TCGNATCT        240                                                                          - TATAAGTCAC TTTTCCCCAA CTCACCAATN CTAGCTAAGA ATTTTTAACC TG - #AGAAAAAC        300                                                                          - AGCTACACTC TAAAATTGCT TCAAAGAAAA TGTCTAACAT ATGGAAAGAA GG - #ACTTAACA        360                                                                          - TGTGAAGCAG ACACTGGCTC CATCTAGTGG GTGCTTTATA TTGAAATAAT TA - #TAATACCT        420                                                                          - CATCAAATTT TTTNGGGTAC AGNTTATTAG GAACTTGGTA TGGAACCAGA TT - #CTGCCACA        480                                                                          #   496                                                                       - (2) INFORMATION FOR SEQ ID NO:80:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 496 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:                                - CATTAGATAA TGGNTCAGGG TGGCCAAGGC TCCGTCTGTC GTTGTGCTCC TG - #CCGTTCTC         60                                                                          - TATTGTCATT CTATAAGCAC AAGAAAAACA TTTTCAGTAA ATCAGATTCT CA - #GCAGAATC        120                                                                          - AAGGTAACGG TTAGACCTGG GATTAACAAC AGACCCGTCA CTATGAGTTC TA - #AAAACCTG        180                                                                          - AAGCAAGAAA AAACAATGTA CAGGAAGTAT GCAGTTTAAA AGTCTAGATT AT - #CTATCATT        240                                                                          - GTTCACTGAA GGCATTCAGG TCCTCTCTTT TACCTGGGTC TTGGNTTGCT CC - #ATTCTCTC        300                                                                          - TGTTCATCCC AACATACACA ATTGTACTTA TCCTTTGAGA TGTACCTTAA AT - #ACTGACAC        360                                                                          - CTGCATGAAA ACTTGTTTAC TGGCTGCAGG TCCAAGCACC TTTTTCNAAA TT - #CAGCTTTC        420                                                                          - TGTGATTTCA GACCACATAT GCAAGGAACT ATCTTACCTT AATTAATAAG AN - #TTTAAAAT        480                                                                          #   496                                                                       - (2) INFORMATION FOR SEQ ID NO:81:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 368 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:                                - AGGANCGCTT GGGCCCAGGA GTTCACAAGC AGCTTGGGCA ACGTAGCAAG AC - #CCTGCCTC         60                                                                          - TATTAAAGAA AACAAAAAAC AAATATTGGA AGTATTTTAT ATGCATGGAA TC - #TATATGTC        120                                                                          - ATGAAAAAAT TAGTGTAAAA TATATATATT ATGATTAGNT ATCAAGATTT AG - #TGATAATT        180                                                                          - TATGTTATNN NGGGATTTCA ATGCCTTTTT AGGCCATTGT CTCAAAAAAT AA - #AAGCAGAA        240                                                                          - AACAAAAAAA GTTGTAACTG AAAAATAAAC ATTTCCATAT AATAGCACAA TC - #TAAGTGGG        300                                                                          - TTTTTGNTTG TTTGTTTGNT TGTTGAAGCA GGGCCTTGCC CTNCCACCCA GG - #NTGGAGTG        360                                                                          #         368                                                                 - (2) INFORMATION FOR SEQ ID NO:82:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 500 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:82:                                - GAATTCCTTT TTTTTTTTTT TTTTTTTTTT TTNCTCCTAA TGTTTTTATT GT - #NCCTTAGA         60                                                                          - TAACTGGATA GNACAAAGTT NGNCTTNGTT TTTTACTTAA AAAACGTACT TT - #CCGCATAC        120                                                                          - TGTNGCCCGT ATGACTTTCC TGTCCCATCG GAAACCAGAG TTTCCCCAGG TG - #AGCCCTTC        180                                                                          - CTATCTGNGG NTACATGATT TAGCTAATTT AACAAGAAGA GAGTAATTCC TT - #NGGATTAT        240                                                                          - TATCAACATG AAACTTGGAC TATGTCTCTA TAAGGGTGAA CACTGATTTT TT - #TTTTCTTT        300                                                                          - TTAGAAACAA AAACCATCCA CTTATTAATC CAAACTACGG GATTGGATTT AC - #AACAATCA        360                                                                          - TCGCATNAAC TGAACATACG AAGTTACCAC TCAAGGGAAT NACAGAAGAA CG - #TTGNACAA        420                                                                          - TNTNTCTTAC GGGGTACGNG AATTCAAACA ATGTGGGGAN AGGAACTTCA NT - #CTACAAAN        480                                                                          #500               GTAT                                                       - (2) INFORMATION FOR SEQ ID NO:83:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 450 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:                                - GAATTCCTTT ACTCTTCTTT AATTCTACCG TCTTTGGGCA TACATCTCAT TT - #GNTGTGGA         60                                                                          - AGAAGGTCTG ACAGNAGGGC TGACAGCACC GATTCATAAC ACATTCTTTT CA - #TCATACAA        120                                                                          - AGAGTAAGAC CCTAGAATAA TGGGACCATC TGCTACCACG ACAGAGCTGC CT - #TACTGGCT        180                                                                          - GTAGAAAAAG ACTGCTTGTG TGGGAGAGAA GAATGAGGAC AGAGGAGGCA TC - #TGGGGCAA        240                                                                          - GTGAGCGTAC AAGTATNTCT ACAAATTCAG AATTTGGTGG AAAATCCAAA TT - #TGNCTTCA        300                                                                          - ACATGATAGA GAATTGATGA GAAAATAGCT GTNCTGTTTC CAAAATTTAC TG - #AATTTGGG        360                                                                          - AACCTGAGGT TAAAACTTTT AGGATNAAGC AACTCAGGTT CAAGACTTNG NC - #TNGGGAAG        420                                                                          #          450     GGGA ATGAGTNTCA                                            - (2) INFORMATION FOR SEQ ID NO:84:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 450 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:                                - CAACTGTATT TATACAGNAA CCACCAGGAG GATAGTCATG ACAACAATGA CA - #AACTAGGA         60                                                                          - ATAGCCCCCT TTCACTTCTG AGTCCCAGAG GTTACCCAAG GCACCCCTCT GA - #CATCCGGC        120                                                                          - CTGCTTCTTC TCACATGANA AAAACTAGCC CCCAGTNTGA TCCGCAGGTN GA - #GGAATNCC        180                                                                          - CCGGGTCGAG GTTCGGATCC TGGATGACAG ACCCTCTCGC CCCTGAAGGN GA - #TAACCGGG        240                                                                          - TGTGGTACAT GGACGGNTAT CACAACAACC GCTTCGNACG TGAGTACAAG TC - #CATGGTTG        300                                                                          - ACTTCATGAA CACGGACAAT TTCACCTCCC ACCGTCTCCC CCACCCCTGG TC - #GGGCACGG        360                                                                          - GGNAGGTGGT CTNCAACGGT TCTTTCTNCT TCAACAAGTT CCAGAGCCAC AT - #CATCATCA        420                                                                          #          450     NAGA GAACATCCTC                                            - (2) INFORMATION FOR SEQ ID NO:85:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 500 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:                                - GGATCCCTCC CCTTTTTAGA CCATACAAGG TAACTTCCGG ACGTTGCCAT GG - #CATCTGTA         60                                                                          - AACTGTCATG GTGTTGGCGG GGAGTGTCTT TTAGCATGCT AATGTATTAT AA - #TTAGCGTA        120                                                                          - TAGTGAGCAG TGAGGATAAC CAGAGGTCAC TCTCCTCACC ATCTTGGTTT TG - #GTGGGTTT        180                                                                          - TGGCCAGCTT CTTTATTGCA ACCAGTTTTA TCAGCAAGAT CTTTATGAGC TG - #TATCTTGT        240                                                                          - GCTGACTTCC TATCTCATCC CGTAACTAAG AGTACCTAAC CTCCTGCAAA TN - #GCAGCCCA        300                                                                          - GTAGGTCTTG GNCTTATTTT ACCCAGCCCC TATTCAAGAT AGAGTTGCTC NT - #GGTCCAAA        360                                                                          - CGCCTCTGAC ACAAGGATTT TAAAGTCTTA TTAATTAAGG TAAGATAGGT CC - #TTGGATAT        420                                                                          - GTGGTCTGAA ATCACAGAAA GCTGAATTTG GAAAAAGGTG CTTGGAGCTG CA - #GCCAGTAA        480                                                                          #500               GTGT                                                       - (2) INFORMATION FOR SEQ ID NO:86:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 500 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:                                - CTGCAGTGAG CCAAAATCGT GCCACTGCAC TTCACTCCAG CCTGGGTGAC AG - #GGCAAGGC         60                                                                          - CCTGCTTCAA CAAACAAACA AACAAACAAA AACCCACTTA GATTGTGCTA TT - #ATATGGAA        120                                                                          - ATGTTTATTT TTCAGTTACA ACTTTTTTTG TTTTCTGCTT TTATTTGTTG AG - #ACAATGGC        180                                                                          - CTAAAAAGGC ATTGAAATNC CAAAATAACA TAAATTATCA CTAAATCTTG AT - #AACTAATC        240                                                                          - ATAATATATA TATTTTACAC TAATTTTTTC ATGACATATA GATTCCATGC AT - #ATAAAATA        300                                                                          - CTTCCAATAT TTGTTTTTTG TTTTCTTTAA TAGAGGCAGG GTCTTGCTAC GT - #TGCCCAAG        360                                                                          - CTGCTTGTGA ACTCCTGGGC CCAAGCGATC CTCCTGCCTC AGCCTCTGAG CC - #TGGCATTA        420                                                                          - CACATGCACC TGGCTTCCTT TTTGTNTTTT TTGAATGTTC CACAGTGAGG AG - #GAAGAAAA        480                                                                          #500               CTCT                                                       - (2) INFORMATION FOR SEQ ID NO:87:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 450 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87:                                - CTGCAGATGA GAGGCACTAA TTATAAGCCA TATTACCTTT CTTCTGACAA CC - #ACTTGTCA         60                                                                          - GCCCACGTGG TTTCTGTGGC AGAATCTGGT TCTATAACAA GTTCCTAATA AG - #CTGTAGCC        120                                                                          - AAAAAAATTT GATGAGGTAT TATAATTATT TCAATATAAA GCACCCACTA GA - #TGGAGCCA        180                                                                          - GTGTCTGCTT CACATGTTAA GTCCTTCTTT CCATATGTTA GACATTTTCT TT - #GAAGCAAT        240                                                                          - TTTAGAGTGT AGCTGTTTTT CTCAGGTTAA AAATTCTTAG CTAGGATTGG TG - #AGTTGGGG        300                                                                          - AAAAGTGACT TATAAGATAC GAATTGAATT AAGAAAAAGA AAATTCTGTG TT - #GGAGGTGG        360                                                                          - TAATGTGGGT GGTGATCTTC ATTAACACTG ANCTAGGGNT TTGGGGTTTG GT - #TTATTGTA        420                                                                          #          450     CANA GAAGATACCG                                            - (2) INFORMATION FOR SEQ ID NO:88:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 502 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:                                - CTGCAGCCAG TAAACAAGTT TTCATGCAGG TGTCAGTATT TAAGGTACAT CT - #CAAAGGAT         60                                                                          - AAGTACAATT GTGTATGTTG GGATGAACAG AGAGAATGGA GCAAGCCAAG AC - #CCAGGTAA        120                                                                          - AAGAGAGGAC CTGAATGCCT TCAGTGAACA ATGATAGATA ATCTAGACTT TT - #AAACTGCA        180                                                                          - TACTTCCTGT ACATTGTTTT TTCTTGCTTC AGGTTTTTAG AACTCATAGT GA - #CGGGTCTG        240                                                                          - TTGTTAATCC CAGGTCTAAC CGTTACCTTG ATTCTGCTGA GAATCTGATT TA - #CTGAAAAT        300                                                                          - GTTTTTCTTG TGCTTATAGA ATGACAATAG AGAACGGCAG GAGCACAACG AC - #AGACGGAG        360                                                                          - CCTTGGCCAC CCTGAGCCAT TATCTAATGG ACGACCCAGG GTAACTCCCG GC - #AGGTGGTG        420                                                                          - GAGCAAGATG AGGAAGAAGA TGAGGAGCTG ACATTGAAAT ATGGCGGCNA GC - #ATGTGATC        480                                                                          #                502GAN TC                                                    - (2) INFORMATION FOR SEQ ID NO:89:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 499 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:                                - CTGCAGTGTT CCTTTTCTCC ACTTAAAACA TGAAGTAATA ACCCCTCGNT CT - #CTCAACTG         60                                                                          - CTCCTGACCA TCACAGAGGA TGGGCTCTCC AGCTAAGTCA TGCCCCTTCA AT - #GNAGAGGC        120                                                                          - CTTCAAGGTG ATGATGACAT GCTGTAAAGA AAAGCCACAC TGGGTTTGAG AA - #TAATAAAA        180                                                                          - CAAAACTCAT ACGTACAGCT GCCCATCCTT CCGGGTATAA AAGCTGACTG AC - #TTAATGGT        240                                                                          - AGCCACGACC ACCACCATGC AGAGAGTCAC AGGGACAAAG AGCATGATCA CA - #TGCTTGGC        300                                                                          - GNCATATTTC AATGTCAGNT CCTCATCTTC TTCCTCATCT TGNTCCACCA CC - #TGCCGGGA        360                                                                          - GTTACCNTGG GTCGTCCATT AGATAATGGG TCAGGGTGGC CAAGGCTCCG TC - #TGTCGTTG        420                                                                          - TGCTCCTGCC GTTCTCTATT GTCATTCTAT AAGCACAAGA AAAACATTTN CA - #GTAAATCA        480                                                                          #499               AAG                                                        - (2) INFORMATION FOR SEQ ID NO:90:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 500 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:                                - TAACTCCCAG GNTCAAGATN TCTNCCTGCG TTAGCCTCCT GAGTAGCTGG GA - #CTATAGGT         60                                                                          - ATGTGCCACT ATTCCTGAAA ACATAATCAG TTTTGAAGGT AGTGTCTGGG CT - #GGGCGCAG        120                                                                          - TGGNTCACGC CTTCAATCCC AGCACTTTGG GAGGNCGAGG TGGGCGGATC AC - #CTGAGGTC        180                                                                          - AGGAGTTCGA GACCAGCCTG ACCAACATGG GATAAGACTC CATCTCTACT AA - #AAATACAA        240                                                                          - AAAATTAGCC AGGCATGGTG GNGCATGCCT GTAATCCCAG CTACTCAGGA GG - #NTGAGGNA        300                                                                          - GGAGAATTGG TTGGAACCTA GGAAGCAGAG GCTGTGGTGG AGCCGAGATC GC - #ACCATTGG        360                                                                          - ACTCCAGGCT GGGNAACAAG AGTGAAAATC CNTCTTAAAA AAAAAAAAAA AA - #AGGTAGNG        420                                                                          - TTTTGNCCGG NGCGGGGGGT CACGCCTGTA ATCCCAGNAT TGGGGANGGC AA - #GGNGGGGG        480                                                                          #500               TCCG                                                       - (2) INFORMATION FOR SEQ ID NO:91:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 502 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:91:                                - GAATTCTGCT GACATGTCCT ATGTTCTTTT CTCCCCTACT CCTTCCTACT GT - #CAGNAATG         60                                                                          - AAGGGTAGGG CTCCAGCCTG GACCCTGAAG TAAGCTAGAG GTTAGAAGCT AA - #AGAAGAAA        120                                                                          - GAAGGAGATT GAGTCCTTNG ATGAACGTGA AGCCACCGTA CTAATCTGGA CT - #GCCTACCT        180                                                                          - CTGCACTACT CTATGAGAGA GAAAGTATGT GCATTATTTA AACCAGTTGG GT - #TGATTTTC        240                                                                          - TATTAACAAA GTCAGAAACA TCTCTGTAAA AAGCCAGACT GAATATTTTA AG - #CTCTATGG        300                                                                          - GTCATATGGT CTCCAGGGCA AACACTCAAC TGTGCTACTG TAGTGTGAAA GC - #AGGCACAG        360                                                                          - ACAATGTATT AACCAAGGAG GGTGGTCACT TTCCAATGAA AGTTTATCAC AA - #ATTGGNGA        420                                                                          - ATACTTGGTA TTACACCNNG GGGGAAGGTA GGAGAAGATC TTGCCTGTGG TT - #GTNGNTGG        480                                                                          #                502ACG NG                                                    - (2) INFORMATION FOR SEQ ID NO:92:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 495 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:                                - GAATTCTCTC CTTAGAAGTT CCATACACAA CACATCTCCC TAGAAGTCAT TG - #CCCTTACT         60                                                                          - TGTTCTCATA GCCATCCTAA ATATAAGGGA GTCAGAAGTA AAGTCTGGNT GG - #CTGGGAAT        120                                                                          - ATTGGCACCT GGAATAAAAA TGTTTTTCTG TGAATGAGAA ACAAGGGGAA GA - #TGGATATG        180                                                                          - TGACATTATC TTAAGACAAC TCCAGTTGCA ATTACTCTGC AGATGAGAGG CA - #CTAATTAT        240                                                                          - AAGCCATATT ACCTTTCTTC TGACAACCAC TTGTCAGCCC ACGTGGTTTC TG - #TGGCAGAA        300                                                                          - TCTGGTTCTA TAACAAGTTC CTAATAAGCT GTAGCCAAAA AAATTTGATG AG - #GTATTATA        360                                                                          - ATTATTTCAA TATAAAGCAC CCACTAGATG GAGCCAGTGT CTGCTTCACA TG - #TTAAGTCC        420                                                                          - TTCTTTCCAT ATGTTAGACA TTTCTTTGAA GCAATTTTAG AGTGTAGCTG TT - #TCTCAGGT        480                                                                          #   495                                                                       - (2) INFORMATION FOR SEQ ID NO:93:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 500 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:                                - TATGGTTGCC TATTCTTGTC ACAGTAACTN AACTGATCTA GGAAAGAAAA AA - #TGTTTTGT         60                                                                          - CTTCTAGAGA TAAGTTAATT TTTAGTTTTC TTCCTCCTCA CTGTGGAACA TT - #CAAAAAAT        120                                                                          - ACAAAAAGGA AGCCAGGTGC ATGTGTAATG CCAGGCTCAG AGGCTGAGGC AG - #GAGGATCG        180                                                                          - CTTGGGCCCA GGAGTTCACA AGCAGCTTGG GCAACGTAGC AAGACCCTGC CT - #CTATTAAA        240                                                                          - GAAAACAAAA AACAAATATT GGAAGTATTT TATATGCATG GAATCTATAT GT - #CATGAAAA        300                                                                          - AATTAGTGTA AAATATATAT ATTATGATTA GTTATCAAGA TTTAGTGATA AT - #TTATGTTA        360                                                                          - TTTTGGGATT TCAATGCCTT TTTAGGCCAT TGTCTCAAAA AAATAAAAGC AG - #GAAAACAA        420                                                                          - AAAAAGTTGT AACTTGAAAA ATAAACATTT CCATATTTAT AGCCAACTAA GT - #GGGTTTNG        480                                                                          #500               TGGT                                                       - (2) INFORMATION FOR SEQ ID NO:94:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 385 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:                                - TTATCATTAA CAGGTCCCAC AACCCTTAAA AAGTACAGAT TTTTTTTTTC TT - #NGTGGAGA         60                                                                          - CAGGGTCTCA CTTGGTCGCC CAGACTGGAG TGCAGTGGCA CGATCTCAGT TC - #ACCACAAC        120                                                                          - CTCTGCCTCC TGGGTTCAAG CAATNCTCGT GCTTAAGCCT CCTGAGTAGG TG - #GAACCACG        180                                                                          - CGTGCGCGCC ACCACGCTAG GTTNATTGTG GCTTTTTTAG TAGAGACAGG GT - #TTCGCCAT        240                                                                          - GTTGCCCAGG CTGGTCTCAN ATTCCNGACC TCAAGTGATC CGNCCGCCTC AG - #ACTCCCAA        300                                                                          - AGTGNTGAGC ATTACAGNTG TGTACCACTA TGTCCCNGNC CNCATCTCTC TT - #TAAAACAN        360                                                                          #              385 CCAC TCCTG                                                 - (2) INFORMATION FOR SEQ ID NO:95:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 330 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:                                - GACCTAGAAA AGAAAGCATT TCAANNTAAT TAACAGGTCC CACAACCCTT AA - #AAAGTACA         60                                                                          - GATTTTTTTT TTCTTTNNGG AGACAGGGTC TCACTTTGTC GCCCAGACTG GA - #GTGCAGTG        120                                                                          - GCACGATCTC AGCTCACCAC ANCCTCTGCC TCCTGGGTTC AAGNANTTCT CG - #TGCTTANG        180                                                                          - CCTCCTGAGT AGGTGGAACC ACGCGTGTGC GCCACCACGC TAGGCTACTT TN - #TGTATTTT        240                                                                          - TAGTAGAGAC AGGGTTTCGC CATNTTGCCC AGGCTGNTCT CAAATTCCTG AC - #CCNCAAGT        300                                                                          #          330     GTAC TCCCCATCAG                                            - (2) INFORMATION FOR SEQ ID NO:96:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 382 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:                                - GGTGGNCGTT CTAGAACTAG TGGCNCCCAA GGNAGAAGAA GTTTTCTTAG TA - #CAGAACAA         60                                                                          - AATGAAANGT CTCCCATGTC TACTTCTTTC TACACAGACA CGGCATCCAT CC - #GTTTTTCT        120                                                                          - CANTCTTTCC NCCACCTTTC CCGTCTTTCT ATTCCACAAA GCCGNCATTG TC - #ATCCTGGC        180                                                                          - CCNTTCTCAA TGAGCTGTTG NNTACACCTC CCAGACGGCG TGGTGGNCGG TC - #AGAGGGGC        240                                                                          - TCCTCACTTC CCAGTAGGGG TGGCCGNGCA GGNGGTGCCC CNCACCCCCC GG - #GCGGGGTG        300                                                                          - GTTNGTCCNN CCGGNGGGNT GCACCNCCCC CACCCCTCCC CNCTCTNCTA CT - #GGCGGTCG        360                                                                          #                382AAG CA                                                    - (2) INFORMATION FOR SEQ ID NO:97:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 360 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:                                - GGATCCAAAG GAAGTTAGAG GCCAGCTCAG TCTACACCTG CTACTGNTCA GT - #GCCCACCC         60                                                                          - GGTCAAGGGA GACCAACACA TGGTAAAGGT CAAGGGCTTC TTGGAAGGCA GT - #CAGCAGCC        120                                                                          - TGTGCAAGAT GTTCTCCACA CTGCTCAGNT TAAGGGGAGC TGGGGGCAGG AC - #CTCAGCTG        180                                                                          - GNATCTCTGC TTCACCAGTG TCCAGGGGTT GCACAATTCT TGTTTACTCG TA - #GGATATTT        240                                                                          - AATCTTGGNN GGTGCTATCA TAAATGGGAC TTATCCNCTN ATTATGTTTT CT - #TACTAGTT        300                                                                          - GTTTATGTGA AGGTTATTGA TTTGGGTTTC ACTTTATTTN GTGGNAATGG AG - #TTTCACTC        360                                                                          - (2) INFORMATION FOR SEQ ID NO:98:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 208 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:                                - AATGTCACGG ATTCCTTTAG GTAGNTACAC CCATCAACCT TTTTGAGAAT AA - #AATGAATT         60                                                                          - GAGAGTGTTA CAGTCTAATT CTATATCACA TGTAACTTTT ATTTGGATAT AT - #CAGTAATA        120                                                                          - GTGCTTTTTT TTTTTTTTTT TTTTTTTTTT TTTTTTTTNG GNGANAGAGT CT - #CGCTCTGT        180                                                                          #            208   AATG GTGCGATC                                              - (2) INFORMATION FOR SEQ ID NO:99:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 470 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:                                - AACAAGGTTT CTCGGTCGGC GGTGAATATA CCGGGGCGTC GATATTTGTT GC - #GGAATACT         60                                                                          - CCCCTGACCG TAAACGTGGC TTTATGGGCA GCTGGCTGGA CTTCGGTTCT AT - #TGCCGGGT        120                                                                          - TTGTGCTGGG TGCGGGCGTG GTGGTGTTAA TTTCGACCAT TGTCGGCGAA GC - #GAACTTCC        180                                                                          - TCGATTGGGG CTGGCGTATT CCGTTCTTTA TCGCTCTGCC GTTAGGGATT AT - #CGGGCTTT        240                                                                          - ACCTGCGCCA TGCGCTGGAA GAGACTCCGG CGTTCCAGCA GNATGTCGAT AA - #ACTGGAAC        300                                                                          - AGGGCGACCG TGAAGGTTTG GAGGATGGCC CGAAAGTCTC GTTTAAAGAG AT - #TGGCACTA        360                                                                          - AATACTGGNG CAGNCTGTTG AATGTTTGGG CTTGGTAATT GGCAACCAAC GT - #GATTACTA        420                                                                          #             470ATATTG CCGAGTTATT GGCGGATAAC CTGAATTATC                      - (2) INFORMATION FOR SEQ ID NO:100:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 440 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:                               - TAATTATATT GAAATGCTTC TCNTCTAGGT CATCCATGNC TGGNTTATTA TA - #TCATCTCT         60                                                                          - ATTGNTGNTG CTCTTTTTTA CATNCATTTA CTTGGGGTAA GTTGTGAAAT TT - #GGGGTCTG        120                                                                          - TCTTTCAGAA TTAACTACCT NNGTGCTGTG TAGCTATCAT TTAAAGCCAT GT - #ACTTTGNT        180                                                                          - GATGAATTAC TCTGAAGTTT TAATTGTNTC CACATATAGG TCATACTTGG TA - #TATAAAAG        240                                                                          - ACTAGNCAGT ATTACTAATT GAGACATTCT TCTGTNGCTC CTNGCTTATA AT - #AAGTAGAA        300                                                                          - CTGAAAGNAA CTTAAGACTA CAGTTAATTC TAAGCCTTTG GGGAAGGATT AT - #ATAGCCTT        360                                                                          - CTAGTAGGAA GTCTTGTGCN ATCAGAATGT TTNTAAAGAA AGGGTNTCAA GG - #AATNGTAT        420                                                                          #440               TGAT                                                       - (2) INFORMATION FOR SEQ ID NO:101:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 449 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:101:                               - AAAACAAAGC CTCTTGAGGT TCTGAAAAGG GAAAGAAAAA CAGAACTTTG TG - #CACTACAA         60                                                                          - TTATACTGTT ATAAAAAACA CTTCCATAGA TTACATTAAG CAGAAACAAA CC - #TTTCTTTC        120                                                                          - ATGTGTTCTC CTCCAGGCCA AGCTGTCTAA GGACCGCAAA GGCTGTTGTC AC - #TTGCAGGC        180                                                                          - TCCCAGATTA GGTCTGAAAT AGGATTTCAC CAGGTCATCC ATTGTTAGTT AA - #ATCCTAGT        240                                                                          - AAATTCATTT ANACCAATCA AATACTTATA AGACCAATTT GTAAACCAGG AA - #TGTATTAA        300                                                                          - TTTGTCACGA CTTTCAACTA ACTGACAAAT TTACTATAAG CTCAAGGTAG GA - #CTCTTTAG        360                                                                          - CAATAAGTAG GAACCGCCTG AGACAACCAA ACATTTTCAA CCCACAAANG AT - #ACTTTAAT        420                                                                          #           449    AGCA AAAGGGGGG                                             - (2) INFORMATION FOR SEQ ID NO:102:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 425 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:102:                               - GGATCCGCCC TCCTCGGCCT CCCAAAGTGT TGGGATTACA GGCGTGAGCC AC - #CGCACCTG         60                                                                          - GCTTTTTTTT TTTTTTTTTT TGGNGGAGAC AGAGTCTTAC TCTGTTGCCC AA - #GCTGGAGT        120                                                                          - GCAGTGGTGC AATCTTGGTT CACTGNAACC TCCACCTCCA GAGTTCAAGC AA - #TTCTCTGC        180                                                                          - CTCAGTTTCT GGAGTAGCTG GGATTACAGG TGCCTGCCAT CACGCCTGGC TA - #AATTTGGN        240                                                                          - ATTTTTTTTT AGTAGAGACA GGGTTTCACC ATGTTGGCCA GGCTGGTCTT GA - #ACTCCTGA        300                                                                          - CCTTGTGATC CACCAGCCTC GGCCTCCCAA ATTGNTGGGA TTACAGGCGT GA - #GCCACCAC        360                                                                          - AACCAGGCTA AAGTTTTAAA ACATGCCAAG TGTATTTACA TAATGCGATA CG - #ANTTATGT        420                                                                          #           425                                                               - (2) INFORMATION FOR SEQ ID NO:103:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 386 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:                               - GGATCCGCCC GCCTTGGCCT CCCAAAGTGC TGGGATTACA GGCATGAGCC AC - #CGCTCCTG         60                                                                          - GCTGAGTCTG CGATTTCTTG CCAGCTCTAC CCAGTTGTGT CATCTTAAGC AA - #GTCACTGA        120                                                                          - ACTTCTCTGG ATTCCCTTCT CCTNTTGTAA AATAAGCATG TTATCTGTCC NN - #CCTGCCTT        180                                                                          - GGGCATTGTG ATAAGGATAA GATGACATTA TAGAATNTNG CAAAATTAAA AG - #CGCTAGAC        240                                                                          - AAATGATTTT ATGAAAATAT AAAGATTAGN TTGAGTTTGG GCCAGCATAG AA - #AAAGGAAT        300                                                                          - GTTGAGAACA TTCCNTTAAG GATTACTCAA GCTCCCTTTG GTGTATATCA GN - #NGTCANNA        360                                                                          #             386  AAAA ATGTTT                                                - (2) INFORMATION FOR SEQ ID NO:104:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 224 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:104:                               - GAAAAGGGAA AGAAAAACAG AACTTTGTGC ACTACAATTA TACTGTTATA AA - #AAACACTT         60                                                                          - CCATAGATTA CATTAAGCAG AAACAAACCT TTCTTTCATG TGTTCTCCTC CA - #GGCCAAGC        120                                                                          - TGTCTAAGGA CCGCAAAGGC TGTTGTCACT TGCAGGCTCC CAGATTAGGT CT - #GAAATAGG        180                                                                          #224               CATT GTTAGTTAAA TCCTAGTAAA TNCA                            - (2) INFORMATION FOR SEQ ID NO:105:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 440 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:105:                               - GGATCCGCCC TCCTCGGCCT CCCAAAGTGT TGGGATTACA GGCGTGAGCC AC - #CGCACCTG         60                                                                          - GCTTTTTTTT TTTTTTTTTT TGGNGGAGAC AGAGTCTTAC TCTGTTGCCC AA - #GCTGGAGT        120                                                                          - GCAGTGGTGC AATCTTGGTT CACTGCAACC TCCACCTCCA GAGTTCAAGC AA - #TTCTCTGC        180                                                                          - CTCAGTTTCT GGAGTAGCTG GGATTACAGG TGCCTGCCAT CACGCCTGGN TA - #AATTTGGG        240                                                                          - ATTTTTTTTT AGTAGAGACA GGGTTTCANC ATGTTGGCCA GGNTGGTCTT GG - #ACTCCTGA        300                                                                          - CCTGGTGAAC CACCAGGCTC GGGCTCCAAA TTTGGTTGGG ATTACAGGGG GT - #NAANCAAC        360                                                                          - CACAACCCAG NCTAAAGTTT TNAAAACATN CAAAGTGTTT TAAAATNATG NG - #ATACGATT        420                                                                          #440               TTAT                                                       - (2) INFORMATION FOR SEQ ID NO:106:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 448 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:106:                               - GTCTTTCCCA TCTTCTCCAC AGAGTTTGTG CCTTACATTA TTACTCCTTG CC - #ATTTTCAA         60                                                                          - GAAAGCATTG TCAGCTCTTC CAATCTCCAT CACCTTTGGG CTTGTTTTCT AC - #TTTGCCAC        120                                                                          - AGATTATCTT GTACAGCCTT TTATGGACCA ATTAGCATTC CATCAATTTT AT - #ATCTAGCA        180                                                                          - TATTTGCGGN TAGAATCCCA TGGATGTTTC TTCTTTGACT ATAACAAAAT CT - #GGGGAGGA        240                                                                          - CAAAGGTGAT TTTCCTGTGT CCACATCTAA CAAAGTCAAG ATCCCCGGCT GG - #ACTTTTGG        300                                                                          - AGGTTCCTTC CAAGTCTTCC TGACCACCTT GCACTATTGG ACTTTGGNAA GG - #AGGTGCCT        360                                                                          - ATAGAAAACG ATTTTGGAAC ATACTTCATC GCAGGGGGAC TGTGTCCCCC GG - #TGGCAGAA        420                                                                          #            448   GGNC GAGGTCAA                                              - (2) INFORMATION FOR SEQ ID NO:107:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 198 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:107:                               - GGATCCGCCC GCCTTGGCCT CCCAAAGTGC TGGGATTACA GGCATGAGCC AC - #CGCTCCTG         60                                                                          - GCTGAGTCTG CGATTTCTTG CCAGCTCTAC CCAGTTGTGT CATCTTAAGC AA - #GTCACTGA        120                                                                          - ACTTCTCTGG ATTCCCTTCT CCTTNAGTAA AATAAGNATG TTATCTGNCC GC - #CCTGCCTN        180                                                                          # 198              AT                                                         - (2) INFORMATION FOR SEQ ID NO:108:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 500 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:108:                               - CTGCAGTGAG CCGTGATTGC ACCACTTTAC TCCAGCCTGG GCAACAAAAT GA - #GACCCTGG         60                                                                          - CTCAAAAACA AAAACAAAAA CAAAAAAAGA GTAAATTAAT TTAAAGGGAA GT - #ATTAAATA        120                                                                          - AATAATAGCA CAGTTGATAT AGGTTATGGT AAAATTATAA AGGTGGGATA TT - #AATATCTA        180                                                                          - ATGTTTGGGA GCCATCACAT TATTCTAAAT AATGTNTTGG TGAAAATTAT TG - #TACATCTT        240                                                                          - TTAAAATCTG TGTAATTTTT TTTCAGGGAA GTGTTTAAAA CCTATAACGT TG - #CTGTGGAC        300                                                                          - TACATTACTG TTGCACTCCT GATCTGGAAT TTTGGGTGTG GTGGGAATGA TT - #TCCATTCA        360                                                                          - CTGGAAAGGT CCACTTCGAC TCCAGCAGGC ATATCTCATT ATGATTAGTG CC - #TCATGGNC        420                                                                          - CTGGTGTTTA TCAAAGTACC TCCCTGAATG GACTGCGTGG GTCATCTTGG NT - #GTGATTCA        480                                                                          #500               AAGA                                                       - (2) INFORMATION FOR SEQ ID NO:109:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 500 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:109:                               - CTGCAGCCTT GACCTCCTGG GATCAATCGA TCCTCCCACC TCAGCCTCCT AA - #GTAGCTGG         60                                                                          - AACTACAGGT GTGCACCACC ATGCCCGGCT AATNGNTGTA TTTTCTGTAG AT - #ACGAGGTN        120                                                                          - TNGCCATGTT GCCCAGGCTG GTCTTGAACT CTGGGCTTAG GTGATCTGCC CG - #CCTCAGCC        180                                                                          - TCCCAAAGTG CTAAGATTAC AGGCATGAGC TACCATGCCC AGCCGAAATC TT - #CAAATGAA        240                                                                          - AAAGTTACTA TAGCTAATTA ATGATTTACT GAAGAGTTAT GGGATGTACA CG - #TTACCATT        300                                                                          - TTCTCTAAAT CAAGATAAAG AGATGAGGAA AGAAAACACT CCAGTGGGGC AT - #TCCTGTNA        360                                                                          - CAAAACAAAT TATCAGTCTT GGGGTTTNAC CATATACTGA AATCACAGGC AA - #GATGAGCC        420                                                                          - ACGCAGTCCA TNCAGGGAGG TACTGGATAA CACCAGGGNC ATGAGGGACT AA - #TCATAATG        480                                                                          #500               TCGA                                                       - (2) INFORMATION FOR SEQ ID NO:110:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 550 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:110:                               - CTGCAGGATG AGAGCGATCT CTTNTTNCAT TTCCTGCGCT ACGCGCTGCG GG - #CGACCAAA         60                                                                          - TTCTTTCGCC ATAATAAATT CTCCTGACNA AAAAGGGGCT GTTAGCCCCT TT - #TTAAAATT        120                                                                          - AATTTCAGGT GGAAGGGCTG TTCACGTTGA CCTGATAAGA CGCGCCAGCG TC - #ACATCAGG        180                                                                          - CAATCCATGC CGGATGCAGC GTAAACGCCT TATCCCGCAT GGAACCCTAA AA - #ACCTTAAG        240                                                                          - CAATGGTACG TTGGATCTCG ATGATTTCGA ATACTTCGAT CACATCGNCA GT - #GCGGACGT        300                                                                          - CGTTGTAGTT CTTAACGCCG ATACCACATT CCATACCGTT ACGGGACTTC GT - #TAACGTCA        360                                                                          - TCTTTGGAAG CGGGGCAGGG ACTCCAGCTC GNCTTCGTAG ATAACCACGT TG - #GCACGCAG        420                                                                          - GAACGCGGGT CGGGTTGTGA CGTTTAACAC AACTTCCGGG TAACCATACA GG - #CTGNGATG        480                                                                          - GNACCAAATT TCGGGGGATT TGGACAAGTC AAGAACTTCC CGCCAGACCG AT - #AATCTTGT        540                                                                          #       550                                                                   - (2) INFORMATION FOR SEQ ID NO:111:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 541 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:111:                               - CTGCAGCTTT CCTTTAAACT AGGAAGACTT GTTCCTATAC CCCAGTAACG AT - #ACACTGTA         60                                                                          - CACTAAGCAA ATAGCAGTCA AACCCAAATG AAATTTNTAC AGATGTTCTG TG - #TCATTTTA        120                                                                          - TNTTGTTTAT GTTGTCTCCC CCACCCCCAC CAGTTCACCT GCCATTTATT TC - #ATATTCAT        180                                                                          - TCAACGTCTN NNTGTGTAAA AAGAGACAAA AAACATTAAA CTTTTTTCCT TC - #GTTAATTC        240                                                                          - CTCCCTACCA CCCATTTACA AGTTTAGCCC ATACATTTTA TTAGATGTCT TT - #TATGTTTT        300                                                                          - TCTTTTNCTA GATTTAGTGG CTGNGTTGTG TCCGAAAGGT CCACTTCGTA TT - #GCTGGTTG        360                                                                          - AAACAGCTCA GGAGAGAAAT GAAACGCTTT TTCCAGCTCT CATTTACTCC TG - #TAAGTATT        420                                                                          - TGGAGAATGA TATTGAATTA GTAATCAGNG TAGAATTTAT CGGGAACTTG AA - #GANATGTN        480                                                                          - ACTATGGCAA TTTCANGGNA CTTGTCTCAT CTTAAATGAN AGNATCCCTG GA - #CTCCTGNA        540                                                                          #              541                                                            - (2) INFORMATION FOR SEQ ID NO:112:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 241 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:112:                               - NNCCCNCNCN NNNNNNNTTN NTNTTGCCCG ATAACTATAG GGNGACTTGG AG - #ATCCACCG         60                                                                          - CGGTGGCGGN CGNTCTAGAA CTAGTGGATC CCCCGGGNTG CAGGACCCAA CG - #CTGCCCGA        120                                                                          - GATGCGCCGC GTGCGGTTGC TGGAGATGGC GGACGCGATG GATATGTTCT GC - #CAAGGGTT        180                                                                          - GGTTTGCGCA TTCACAGTTC TCCGCAAGAA TTGATTGGCT CCAATTCTTG GA - #GTGGTGAA        240                                                                          #              241                                                            - (2) INFORMATION FOR SEQ ID NO:113:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 834 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:113:                               - CCCCCCCNCC NNNNNTTTTN NGCAGCCCGT AATTACCCTC ACTNCCGGGA AC - #AAAAGCTG         60                                                                          - GGTACCGGGC CCCCCCTCGA GGTCGACGGT ATCGATAAGC TTGATATCGA AT - #TCCTGCAG        120                                                                          - TGTTTAAAAA ATAAAATAAA CTAAAAGTTT ATTTATGAGG AGTACACTGC TT - #TCTTGTAA        180                                                                          - ACACATGTAC AAGCCATATA ATAGAGTTCA TTTTTTACCC TAGTTACGGA AA - #CACTAGAA        240                                                                          - AGTCTTCACC CGGCCAAGAT AACACATCTT TAGTAAAAAT AGCAAGAAAT AT - #TTTATGGG        300                                                                          - TTGTTTACTT AAATCATAGT TTTCAGGTTG GGCACAGTGG NTCATGCCTG TA - #ATCCCAGC        360                                                                          - ACTTTATGCG GNTGAGGCAG GCAGATCAGT TGAGGTCAGA AGTTTGGAGA CC - #AGNCTGGG        420                                                                          - CAATGTGGNA AAACCTCATC TCCACTAAAA ATACAAAAAT TAGNCAGGCA TG - #GTGGTGCA        480                                                                          - CACATGTAAT TCCAGNTACT TGGGGAGGCT GAGACAGGAG GATCGNTTGA AC - #CTAGGGAG        540                                                                          - GGAGGAGTTG GAGTGAGCTA ATGTCAATGC ACTCTTGGTT GGGGCGANAG AG - #CAAGATCT        600                                                                          - TTCTTCCAAA AAAAAAAAAA AAAAAAAAGC CAGGTGNGGN GGTCAAGGCT GT - #AATCCAGA        660                                                                          - ATTNGGGAGG CCGNGGAGGN NATCANTGNG GNAGGNGTCA AGNGGGGCNG GC - #CACATGGG        720                                                                          - GAACCCGTTN TTNTTAAATN AAAATTAGCC GGGGNGGGGG AGGACTNTAT CC - #NGTTCCGG        780                                                                          - NGGTGNGGAG GATCNTTATT NTGGNGGAGG GTGGATGNNC CAGTTGACNC CC - #CC              834                                                                          - (2) INFORMATION FOR SEQ ID NO:114:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 838 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:114:                               - TTGGGCNCNC GCCCCTTAAN TTTTTATNGN TTNCTANAAA AANANNNGGC NC - #NNTAAAAT         60                                                                          - ATATTTTTTN TTGTGACCCC TTTTAAAAGG GACCCNCTAA AAAATTTTNT GG - #TTNNTTTN        120                                                                          - GATTTANGTG GGTGNTTTTN TTATATTTTT GGNGAGNNTC TGTAGTCNTC NC - #CCTCAAAC        180                                                                          - ANNTCNTACN ATNGGNANCG TGACTCTGTC NTTNGTNANN NTCGNTNTCN NG - #TNATTCNA        240                                                                          - GGNNCCTCGC GCNNCNCGGG CNNNGTTTTT TTTNNCNNTT TTTAAGCCNA AN - #NCTCAGTA        300                                                                          - NCNTCCAACG GNGCTNNGAC ANNNGNNNCT NTCGNGGGTN CCCTCTNTNT NG - #NNCNNGGC        360                                                                          - TNNNGNNNNC NGNCNGCNGN GCCNTGCGNN NNGNNNGNGG NNNGNTNNCA TA - #NGGATNGN        420                                                                          - GNTGCTCNNC NCNNGNGTNN TNAGTAGGNA NTTTTNTNNT ACTTGCCNNC NN - #NTNGCTGC        480                                                                          - GAGNANAGCN ANNTNGNNGN AGNGNNGNTG CGCGGANNTT CCCCTGATNA NC - #TCGAGCNG        540                                                                          - NTTACNGGNG CNNCCTNGAA NAAGNGNNGT ANNGTGCCGA GNCGCTANNC TG - #AGCCTGAG        600                                                                          - TNTCGACNGG NATNGTGNNT CNTACNGTTA NGGGNNGCNN GANCGGGNTG AN - #TCNCCGGN        660                                                                          - NGANCNAGCG ACTGCCTNTC ANGCGAANCG TNTCANGNNN GTAGAGCANA GG - #GTNANNNG        720                                                                          - TCNNNNAAGC NTNNAGTGAN TGTCNTNACN NGTGANTTAC GGCNTAGNCT TG - #ATNTNNAN        780                                                                          - NCGAGGNNNN ATNNANNNTT GGANANTTNN TNNNNTCNCN TCGCGGNGNG NC - #NNGCCG          838                                                                          - (2) INFORMATION FOR SEQ ID NO:115:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 803 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:115:                               - ATTCGCGCGT AGCCCGATAA CTATAGGGCG ACNTGGAGNT CCACCGCGGT GG - #CGGCCGCT         60                                                                          - CTAGNAACTA GTGGATCCCC CGGGCTGCAG GAATTCACGG ACTAATCCTC TA - #CAGATCTT        120                                                                          - GCTGGAGTGG CCTTTCAGCC TTTTGTGACT GTTTGTAGTG AAATGTACAC AC - #AAGCCTAC        180                                                                          - AAGGCAGCCC AGATGTACCA TAACTGTGGG AAAATTAAAA AAAAAAAAAC AC - #AGAACCTC        240                                                                          - TCTATGTTGC CCATGCTGGA CTCAAACTCT TAGACAAGCA ATCCTCGTAC CT - #CAGCCTCC        300                                                                          - TGAGTTCCTG AGTAGCTGGG ACTACAAGCA TGCACCACCA TGCCAGGCTA TG - #AGAAAGTT        360                                                                          - CTTTTTATTG ATCCAGACCT TATTGCCTGG TAACTTCCAC CACTGTTCCT AG - #CTCTGNTC        420                                                                          - TCTGGTCCTA ACAGAGGAAA ATCTTGACCC CACACCTAGT GCAACTGGAT AG - #CTTATNGT        480                                                                          - TGGGCTNGTG TTTCCTCTAT TCTGGGTCCA CCCTAAAATC CNATAGATAC TC - #CAACTGCT        540                                                                          - CANAGNAAAC CAAGCTCTCT CTCTNNCTTN CTTTCTTNNN CTCTATTNAT TN - #ATGGGNNA        600                                                                          - TNATTNATTN NGGGGATGGN GTTCGGTCGC CGCCCGGCTG GNGTGAAATG GG - #GGAGGCAA        660                                                                          - TCAATTTAAC CCCACCCNGG GTCCAGGGAT CTCGTTNAAA CCGNNNNNNN NN - #NNNNNNNA        720                                                                          - NGNNCNNCNC NNNCCNNTNN NNNGGTTTNN NNGNNNNGGG NNNCCNNNNN NA - #NNNNNNTN        780                                                                          #               803NNNN CCC                                                   - (2) INFORMATION FOR SEQ ID NO:116:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 780 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:116:                               - CNNNNNNNCC CNNTNATTNT ACGCCAGCCG CGTAATTAAC CCTCACTAAA GG - #GAACAAAA         60                                                                          - GCTGGGTACC GGGCCCCCCC TCGAGGTCGA CGGTATCGAT AAGCTTGATA TC - #GAATTCCA        120                                                                          - ACTCCTCACT TGCCAGATGT GACCTTAAGC AAGTGAACTT CTGTGTGCCA CA - #CTGTTTTC        180                                                                          - ATCTGTAAAA GGATAAAGGG AATATCATAA ATTAGNTTGT TAAGCCTTAG TT - #TAATAATG        240                                                                          - TCTCTAAGTT TTACATATAA GTAGACAGTG TCTTTCTTGT TTAGTGAATA AT - #CATTCTTA        300                                                                          - TTATTTAATA GTATCTCTAC TAAATTTATT GTGTAAGATT ATACTAATCT TG - #TTTAGTGC        360                                                                          - GTGGTAATCA CTTCTGCTCA TATTTAACCT ATAAGCATAA TATAGTTTAT TT - #ATATACCA        420                                                                          - NTTATTTATT TTATTTTATT TGNNGAGATG CAGCTTGTCT TTTNCAACCC AG - #GGNTGNGG        480                                                                          - NGNAGNNGNG NAANCTTGNT TCACTGNAAC CNCCACCNCC CAGGTNCAAG NG - #ATTCTCCT        540                                                                          - GNTCAAGCCN CCTNAGNAGN TGGNATTACA GNACGANTAC ANNCCAGNTA NN - #NNGGNTNT        600                                                                          - NNGNTNGNNA GGNNNCACAN NNGNCAGGTN NNTCGNCTCC NNGCCANTNA CT - #NNNNCCAN        660                                                                          - CCCCNNNGNN NNNNATANAG NATNANCANN NNCCNCNNNN NCNNNNNNNG GN - #GGANNCCN        720                                                                          - NNTNGCNGNN ANNGNNANNN NNTNNNNNNN NNGGNCNNNG NNNNNNNNCC NN - #NNNNCCCC        780                                                                          - (2) INFORMATION FOR SEQ ID NO:117:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 803 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:117:                               - NNNNNNNNNC CNNNNNNTTC GNNCGTAACN CGANTCACTA TAGGGCGACT TG - #GAGCTCCA         60                                                                          - CCGCGGTGGC GGCCGCTCTA GAACTAGTGG ATCCCCCGGG CTGCAGGAAT TC - #GATATCAA        120                                                                          - GCTTTNGTGT GTAAAAAGTA TTAGAATCTC ATGTTTTTGA ACAAGGTTGG CA - #GTGGGTTG        180                                                                          - GGAGGAGGGA TTGGAGATTG ATGCGATAGG AATGTGAAGG GATAGCTTGG GG - #TGGATTTT        240                                                                          - ATTTTTTAAT TTTAATTTTT ATTTNTTGAG ATGGAGTCTT GCTCTGTCTC CC - #AGGCTGGA        300                                                                          - GTGCAGTGGT GTGATCTCAG CTCACGGGTT CAAGCGATTC TCCTGCTGCA GC - #CTCCCGAG        360                                                                          - TAGCTGGGAT TACAGGAGCG CGCCACCACA CCCGGNTAAT TTNNTTGTAT TT - #TTAGTAGA        420                                                                          - GACGGGGTTT CACCATGTTG GTTAGGCTGG TCTAGAACTC CCAACCTCAT GA - #TCCGCCTG        480                                                                          - CTTCGGCCTC CCAAAGTGCC GGAATTACAG GCGTGAGCGA CTGCACCCGG CC - #GCTTGGGG        540                                                                          - GTGGATTTTT AAAGAAATTT AGAAGAATGT AACTTGGCCA GATACCATGT AC - #CCGTTAAT        600                                                                          - TCATTTNCGG TTTTTTGGAT ACCCATTTTG NNATTCTCCC NCCACTGGAT AA - #ATAAGGGN        660                                                                          - GGTTCATTNT NGNTTAGTTT GGGTNTTTTT NAGTGTGGNT TCTGCTTATN AT - #TAGAATGG        720                                                                          - NCTNCTTTNC CAANCTGGAA AGGGAGGAGT TAAAATCANT ACCAGAANCA GA - #AATTCTTT        780                                                                          #               803AAAT GCC                                                   - (2) INFORMATION FOR SEQ ID NO:118:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 819 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:118:                               - TNCCNNNNCN NNNNNAATTT TNGCAGNCGC GTAATTAACC TCACTAAAGG GA - #ACAAAAGC         60                                                                          - TGGGTACCGG GCCCCCCCTC GAGGTCGACG GTATCGATAA GCTTCCCTCC CC - #TTCCTCAG        120                                                                          - CTCTGGCGAC CCTGCGCTGT GGTGGTTCTC CAACCACACT CATTCTCCTC AG - #CTGGCTCC        180                                                                          - TTGCTCTTCT TCCACCCCCT CGTTGGAAGT GTTCCTAAGT GTTTGGCTTG GC - #CTCCTCTT        240                                                                          - CCCCTTCCTT AGNTTAGACT TCTCCACTGC TCCAACATCA ACTGGAAATC TA - #TGGAATTG        300                                                                          - ATTCCTGTTT TCAGCTCCAG TCCTGTTCAC AGGGCATTTT CACCTGCTGG CA - #CTTCCAAA        360                                                                          - GTGACACTTC CAAACCACTT CCTCGCCCTC CTCTCTAAAC CAGGTCTTTC TT - #CCTAACTT        420                                                                          - CCTTATTTCT GAGAATGTCT CTGNCATGTT CTAAACTGAA AACTCCTAGT CA - #ACTNCACA        480                                                                          - CTTTATTCCC TGGATCCTCA ATTGGGTTCC CATGTNCCGT TAGTGTTTCT TG - #GTAAGNCT        540                                                                          - CTGCCANCAC CGNAGGATCG ACTCTAATCA CATCTCAACT GAATTATGGN AA - #AGTCAACT        600                                                                          - CAATTCTCTC AACCATCCCA GGCTCCACTA TGGNTAATAT GCTAAGGAGA GC - #TGACCCAA        660                                                                          - CGGGGAGAAG ATCTGNGGGG GAGGAGAGAA ACAAAGNTAA TGGAATNATT CT - #CGAAAAGC        720                                                                          - CCACAAGGNG AAGGATAACC CNCTTCCNCT CGAAAGAGGG GGGATCGCCA GA - #TNTCGCGC        780                                                                          #   819            GNGA GGGGGTTACA NTGTAAGNC                                  - (2) INFORMATION FOR SEQ ID NO:119:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 796 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:119:                               - TNTTGGCTGG TACTGCTTGA GCAACTGGTG AAACTCCGCG CCTCACGCCC CG - #GGTGTGTC         60                                                                          - CTTGTCCAGG GGCGACGAGC ATTCTGGGCG AAGTCCGCAC GCCTCTTGTT CG - #AGGCGGAA        120                                                                          - GACGGGGTCT GATGCTTTCT CCTTGGTCGG GACTGTCTCG AGGCATGCAT GT - #CCAGTGAC        180                                                                          - TCTTGTGTTT GCTGCTGCTT CCCTCTCAGA TTCTTCTCAC CGTTGTGGTC AG - #CTCTGCTT        240                                                                          - TAGGCATATT AATCCATAGT GGAGGCTGGG ATGGGTGAGA GAATTGAGGT GA - #CTTTTCCA        300                                                                          - TAATTCAGGT GAGATGTGAT TAGAGTTCGA TCTGCGGTGG TGGCAGAGGC TT - #ACAAGAAA        360                                                                          - CACTAACGGG ACATGGGAAC CAATTGAGGA TCAGGGAATA AAGTGTGAAG TT - #GACTAGGA        420                                                                          - GGTTTTCAGT TTAGAACATG GCAGAGACAT TCTCAGAAAT AAGGAAGTTA GG - #AAGAAAGA        480                                                                          - CTGGTTTAGA GAGGAGGGCG ANGAAGTGGT TTGGGAAGTG TCACTTTGGG AA - #GTGCCAGC        540                                                                          - AGGTGAAAAT GCCTGTGACA GGATGGAGCT GAAAACAGGA TCAATTCCAT AG - #ATTCCAGT        600                                                                          - TGATGTNGGA GCAGGGGAGA AGTCTTAGCT AAGGAAGGGG AAGAGGAGGC CA - #AGGNAACA        660                                                                          - CTTAGGACAA TTGNAACGAN GGGGGGGGAG AAGAGNAAGG GCCACTTAGG GG - #AATAATNT        720                                                                          - GGTGGGGGAC CCCCAAGNNA GGGCGCANNN TTAGGAGGGG GGGANNTCAN AG - #GAAAGTGG        780                                                                          #   796                                                                       - (2) INFORMATION FOR SEQ ID NO:120:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 802 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:120:                               - ATTCGTCGTA NCCCGATNAC TATAGGGCGA CTTGGAGCTC CACCGCGGTG GC - #GGNCGCGG         60                                                                          - GCAGGGNCCG GNCCTTTGTG GCCGCCCGGG CCGCGAAGCC GGTGTCCTAA AA - #GATGAGGG        120                                                                          - GCGGGGCGCG GNCGGTTGGG GCTGGGGAAC CCCGTGTGGG AAACCAGGAG GG - #GCGGCCCG        180                                                                          - TTTCTCGGGC TTCGGGCGCG GCCGGGTGGA GAGAGATTCC GGGGAGCCTT GG - #TCCGGAAA        240                                                                          - TGCTGTTTGC TCGAAGACGT CTCAGGGCGC AGGTGCCTTG GGCCGGGATT AG - #TAGCCGTC        300                                                                          - TGAACTGGAG TGGAGTAGGA GAAAGAGGAA GCGTCTTGGG CTGGGTCTGC TT - #GAGCAACT        360                                                                          - GGTGAAACTC CGCGCCTCAC GCCCCGGGTG TGTCCTTGTC CAGGGGCGAC GA - #GCATTCTG        420                                                                          - GGCGAAGTCC GCACGCCTCT TGTTCGAGGC GGAAGACGGG GTCTTGATGC TT - #TCTCCTTG        480                                                                          - GGTCGGGGAC TGTCTCGAGG CATGCATGTC CAGTGACTCT TGTGTTTGGT GN - #TGCTTCCC        540                                                                          - TCTCAGATCT TCTCACCGNG GTGGGCAACT CTGTTTAGGC ATATTATCCA TA - #GNGGAGGC        600                                                                          - TGGATGGTTG AAANAATTGA GGTNATTTTC CATAATCAAG TGAAATTTGA TA - #GAGTCCGN        660                                                                          - CTTTNGGGGT GNAAGGGTTA AAAAAAAATA ACGGAAATGG AACAATGAGG TC - #AAGGATTA        720                                                                          - GTTGAGTTGN TAGNGGTTCA ATTAGANATG AAGGNATCTA AAATAGGAGT AG - #AGAANNNG        780                                                                          #                802TTG CC                                                    - (2) INFORMATION FOR SEQ ID NO:121:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 793 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:121:                               - ATATGCAGCC GCGTAATTAA CCTCACTAAA GGGAACAAAA GCTGGGTACC GG - #GCCCCCCC         60                                                                          - TCGAGGTCGA CGGTATCGAT AAGCTTGATA TCGAATTCCT GCAGCCCGGG GG - #ATCCGCCC        120                                                                          - CGCGGCCTCC CAAAGTGCTG GGATTACAGG CGTGAGCCAC CGCCCCGGGN CT - #CACATTTT        180                                                                          - ATTTCTATTG GCTAGCGCTG CTCTAAATCT TCTGTTCCTT CTGCTACACC AG - #GCCTAACA        240                                                                          - CTCAAAATCC CTGCCAACCT TTTCCTTCCT GAAGCTTCCC TCCCCTTCCT CA - #GCTCTGGC        300                                                                          - GACCCTGCGC TGTGGTGGTT CTCCAACCAC ACTCATTCTC CTCAGCTGGC TC - #CTTGCTCT        360                                                                          - TCTTCCACCC CCTCGNTGGA AGTGTTCCTA AGTGTTTGGC TTGGCCTCCT CT - #TCCCCTTC        420                                                                          - CTTAGCTTAG ACTTCTCCAC TGCTCCAACA TCAACTGGAA ATCTATGGAA TT - #GATTCCTG        480                                                                          - TTTCAGCTCC AGTCCTGTTC ACAGGGGATT TTCANCTGGT GGCATTTCCA AA - #GTGAAATT        540                                                                          - CCAAACCACT TCCTCGGCCT CCTCTTCTAA ANCAGGTCTT TCTTCCTAAC TT - #CCTTATTC        600                                                                          - TTGAGAATGT CTCTGCATGT TCTTAAANTG AAAACTCCTA GTCAAATTCA AA - #TTTATCCC        660                                                                          - TGATCCCAAA TGGTCCCATT CCCGTAGGGT TTNTGTAGCC TGCACACCGA GG - #TCGGANTT        720                                                                          - TATNNATTCA CCGATTATGG AAAGTAACCA ATCTTNACCA NCCAGCTCAT TT - #GTTNTNTG        780                                                                          #     793                                                                     - (2) INFORMATION FOR SEQ ID NO:122:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 440 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:122:                               - AAAGTCATGG ATTCCTTTAG GTAGCTACAT TATCAACCTT TTTGAGAATA AA - #ATGAATTG         60                                                                          - AGAGTGTTAC AGTCTAATTC TATATCACAT GTAACTTTTA TTTGGATATA TC - #AGTAATAG        120                                                                          - TGCTTTTTCN TTTTTTTTTT TTNTTTTTTT TNNTTTTNGG GGANAGAGTC TC - #GCTCTGTC        180                                                                          - GCCAGGTTGG AGTGCAATGG TGCGATCTTG GCTCACTGAA AGCTCCACCN CC - #CGGGTTCA        240                                                                          - AGTGATTCTC CTGCCTCAGC CNCCCAAGTA GNTGGGACTA CAGGGGTGCG CC - #ACCACGCC        300                                                                          - TGGGATAATT TTGGGNTTTT TAGTAGAGAT GGCGTTTCAC CANCTTGGNG CA - #GGCTGGTC        360                                                                          - TTGGAACTCC TGANATCATG ATCTGCCTGC CTTAGCCTCC CCAAAGTGCT GG - #GATTNCAG        420                                                                          #440               CTGG                                                       - (2) INFORMATION FOR SEQ ID NO:123:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 453 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:123:                               - CTTAGTCTGT NTCGTAGTCA TATTAATTGT AAGTNTACAC TAATAAGAAT GT - #GTCAGAGC         60                                                                          - TCTTAATGTC AAAACTTTGA TTACACAGTC CCTTTAAGGC AGTTCTGTTT TA - #ACCCCAGG        120                                                                          - TGGGTTAAAT ATTCCAGCTA TCTGAGGAGC TTTTNGATAA TTGGACCTCA CC - #TTAGTAGT        180                                                                          - TCTCTACCCT GGCCACACAT TAGAATCACT TGGGAGCTTT TAAAACTGTA AG - #CTCTGCCC        240                                                                          - TGAGATATTC TTACTCAATT TAATTGTGTA GTTTTTAAAA TTCCCCAGGA AA - #TTCTGGTA        300                                                                          - TTTCTGTTTA GGAACCGCTG CCTCAAGCCT AGCAGNACAG ATATGTAGGA AA - #TTAGCTCT        360                                                                          - GTAAGGTTGG TCTTACAGGG GATAAACAGA TCCTTCCTTA GNCCCTGGGA CT - #TAATCACT        420                                                                          #        453       GTTT NGNATTTAAT GAC                                        - (2) INFORMATION FOR SEQ ID NO:124:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 369 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:124:                               - GACACACATT CACACATAAT TATGAAAGCA TTTTCAGGCA AAACTCAATC AC - #AAGTCTGG         60                                                                          - GTTTTTAACA TAGTTAACTG AATATTTCCC TTGGGGGGTT AAATTTTAGA AC - #AGACGTNC        120                                                                          - ATNCAATCTG GAAGAAGAGC TATGAAAAAA ACCTAGCTTG GGTNGGTTTC AT - #AGGGTNCA        180                                                                          - TTATGNACAC ATTGTTATTT TATCCCTTAA TNCTAGTAAA GAAATAGAAT CT - #GAAAATAA        240                                                                          - GTAAAACTAC TTGGAAAAAA NTTAAAAGAT ACAGAAATTT CTATCTTAAA TG - #ATGTGTGG        300                                                                          - GCCNCTGTGA TTTTAGTNGG GNTGGTTAAA ANCCCAGAGG TGAAGAGNAT NC - #TCTATGCT        360                                                                          #        369                                                                  - (2) INFORMATION FOR SEQ ID NO:125:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 516 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:125:                               - GCTCATCATG CTTCACGGGG GAGGCTGTGC GGGAAGAATG CTCCCACACA GN - #ATAAAGAA         60                                                                          - TGCTCCCGCA CAGGATAGAG AATGCCCCCG CACAGCATAG AGAAGCCCCC GC - #ACAGCATA        120                                                                          - GAGAATGCCC CCNCACAGCA TAGAGAAGCC CCCGCACAGC ATAGAGAATG CT - #CTTCACCT        180                                                                          - CTGGGTTTTT AACCAGCCAA ACTAAAATCA CAGAGGSCMA CACATCATTT AA - #GATAGAAA        240                                                                          - TTTCTGTATC TTTTAATTTY TTTCMAAGTA GTTTTACTTA TTTTCAGATT CT - #ATTTCTTT        300                                                                          - ACTAGAATTA AGGGATAAAA TAACAATGTG TGCATAATGA ACCCTATGAA AC - #MAACMMAA        360                                                                          - GCTAGGTTTT TTTCATAGST CTTCTTCCAG ATTGAATGAA CGTCTGTTCT AA - #AATTTAAC        420                                                                          - CCCCCAGGGA AATATTCAGT TAACTATGTT AAAAACCCAG ACTTGTGATT GA - #GTTTTGCC        480                                                                          #      516         ATTA TGTGTGAATG TGTGTC                                     - (2) INFORMATION FOR SEQ ID NO:126:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 121 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:126:                               - GTATAATGCA GGTGCTATAA GGTGAGCATG AGACACAGAT CTTTGCTTTC CA - #CCCTGTTC         60                                                                          - TTCTTATGGT TGGGTATTCT TGTCACAGTA ACTTAACTGA TCTAGGAAAG AA - #AAAATGTT        120                                                                          #              121                                                            - (2) INFORMATION FOR SEQ ID NO:127:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 18 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:127:                               #  18              AC                                                         - (2) INFORMATION FOR SEQ ID NO:128:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 21 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:128:                               #21                GAAC T                                                     - (2) INFORMATION FOR SEQ ID NO:129:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 19 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:129:                               # 19               TCT                                                        - (2) INFORMATION FOR SEQ ID NO:130:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 21 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:130:                               #21                ATGA G                                                     - (2) INFORMATION FOR SEQ ID NO:131:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 19 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:131:                               # 19               AGC                                                        - (2) INFORMATION FOR SEQ ID NO:132:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 19 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA (genomic)                                       -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:132:                               # 19               AGC                                                        - (2) INFORMATION FOR SEQ ID NO:133:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 2791 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:133:                               - TGGGACAGGC AGCTCCGGGG TCCGCGGTTT CACATCGGAA ACAAAACAGC GG - #CTGGTCTG         60                                                                          - GAAGGAACCT GAGCTACGAG CCGCGGCGGC AGCGGGGCGG CGGGGAAGCG TA - #TACCTAAT        120                                                                          - CTGGGAGCCT GCAAGTGACA ACAGCCTTTG CGGTCCTTAG ACAGCTTGGC CT - #GGAGGAGA        180                                                                          - ACACATGAAA GAAAGAACCT CAAGAGGCTT TGTTTTCTGT GAAACAGTAT TT - #CTATACAG        240                                                                          - TTGCTCCAAT GACAGAGTTA CCTGCACCGT TGTCCTACTT CCAGAATGCA CA - #GATGTCTG        300                                                                          - AGGACAACCA CCTGAGCAAT ACTGTACGTA GCCAGAATGA CAATAGAGAA CG - #GCAGGAGC        360                                                                          - ACAACGACAG ACGGAGCCTT GGCCACCCTG AGCCATTATC TAATGGACGA CC - #CCAGGGTA        420                                                                          - ACTCCCGGCA GGTGGTGGAG CAAGATGAGG AAGAAGATGA GGAGCTGACA TT - #GAAATATG        480                                                                          - GCGCCAAGCA TGTGATCATG CTCTTTGTCC CTGTGACTCT CTGCATGGTG GT - #GGTCGTGG        540                                                                          - CTACCATTAA GTCAGTCAGC TTTTATACCC GGAAGGATGG GCAGCTAATC TA - #TACCCCAT        600                                                                          - TCACAGAAGA TACCGAGACT GTGGGCCAGA GAGCCCTGCA CTCAATTCTG AA - #TGCTGCCA        660                                                                          - TCATGATCAG TGTCATTGTT GTCATGACTA TCCTCCTGGT GGTTCTGTAT AA - #ATACAGGT        720                                                                          - GCTATAAGGT CATCCATGCC TGGCTTATTA TATCATCTCT ATTGTTGCTG TT - #CTTTTTTT        780                                                                          - CATTCATTTA CTTGGGGGAA GTGTTTAAAA CCTATAACGT TGCTGTGGAC TA - #CATTACTG        840                                                                          - TTGCACTCCT GATCTGGAAT TTTGGTGTGG TGGGAATGAT TTCCATTCAC TG - #GAAAGGTC        900                                                                          - CACTTCGACT CCAGCAGGCA TATCTCATTA TGATTAGTGC CCTCATGGCC CT - #GGTGTTTA        960                                                                          - TCAAGTACCT CCCTGAATGG ACTGCGTGGC TCATCTTGGC TGTGATTTCA GT - #ATATGATT       1020                                                                          - TAGTGGCTGT TTTGTGTCCG AAAGGTCCAC TTCGTATGCT GGTTGAAACA GC - #TCAGGAGA       1080                                                                          - GAAATGAAAC GCTTTTTCCA GCTCTCATTT ACTCCTCAAC AATGGTGTGG TT - #GGTGAATA       1140                                                                          - TGGCAGAAGG AGACCCGGAA GCTCAAAGGA GAGTATCCAA AAATTCCAAG TA - #TAATGCAG       1200                                                                          - AAAGCACAGA AAGGGAGTCA CAAGACACTG TTGCAGAGAA TGATGATGGC GG - #GTTCAGTG       1260                                                                          - AGGAATGGGA AGCCCAGAGG GACAGTCATC TAGGGCCTCA TCGCTCTACA CC - #TGAGTCAC       1320                                                                          - GAGCTGCTGT CCAGGAACTT TCCAGCAGTA TCCTCGCTGG TGAAGACCCA GA - #GGAAAGGG       1380                                                                          - GAGTAAAACT TGGATTGGGA GATTTCATTT TCTACAGTGT TCTGGTTGGT AA - #AGCCTCAG       1440                                                                          - CAACAGCCAG TGGAGACTGG AACACAACCA TAGCCTGTTT CGTAGCCATA TT - #AATTGGTT       1500                                                                          - TGTGCCTTAC ATTATTACTC CTTGCCATTT TCAAGAAAGC ATTGCCAGCT CT - #TCCAATCT       1560                                                                          - CCATCACCTT TGGGCTTGTT TTCTACTTTG CCACAGATTA TCTTGTACAG CC - #TTTTATGG       1620                                                                          - ACCAATTAGC ATTCCATCAA TTTTATATCT AGCATATTTG CGGTTAGAAT CC - #CATGGATG       1680                                                                          - TTTCTTCTTT GACTATAACC AAATCTGGGG AGGACAAAGG TGATTTTCCT GT - #GTCCACAT       1740                                                                          - CTAACAAAGT CAAGATTCCC GGCTGGACTT TTGCAGCTTC CTTCCAAGTC TT - #CCTGACCA       1800                                                                          - CCTTGCACTA TTGGACTTTG GAAGGAGGTG CCTATAGAAA ACGATTTTGA AC - #ATACTTCA       1860                                                                          - TCGCAGTGGA CTGTGTCCCT CGGTGCAGAA ACTACCAGAT TTGAGGGACG AG - #GTCAAGGA       1920                                                                          - GATATGATAG GCCCGGAAGT TGCTGTGCCC CATCAGCAGC TTGACGCGTG GT - #CACAGGAC       1980                                                                          - GATTTCACTG ACACTGCGAA CTCTCAGGAC TACCGGTTAC CAAGAGGTTA GG - #TGAAGTGG       2040                                                                          - TTTAAACCAA ACGGAACTCT TCATCTTAAA CTACACGTTG AAAATCAACC CA - #ATAATTCT       2100                                                                          - GTATTAACTG AATTCTGAAC TTTTCAGGAG GTACTGTGAG GAAGAGCAGG CA - #CCAGCAGC       2160                                                                          - AGAATGGGGA ATGGAGAGGT GGGCAGGGGT TCCAGCTTCC CTTTGATTTT TT - #GCTGCAGA       2220                                                                          - CTCATCCTTT TTAAATGAGA CTTGTTTTCC CCTCTCTTTG AGTCAAGTCA AA - #TATGTAGA       2280                                                                          - TTGCCTTTGG CAATTCTTCT TCTCAAGCAC TGACACTCAT TACCGTCTGT GA - #TTGCCATT       2340                                                                          - TCTTCCCAAG GCCAGTCTGA ACCTGAGGTT GCTTTATCCT AAAAGTTTTA AC - #CTCAGGTT       2400                                                                          - CCAAATTCAG TAAATTTTGG AAACAGTACA GCTATTTCTC ATCAATTCTC TA - #TCATGTTG       2460                                                                          - AAGTCAAATT TGGATTTTCC ACCAAATTCT GAATTTGTAG ACATACTTGT AC - #GCTCACTT       2520                                                                          - GCCCCCAGAT GCCTCCTCTG TCCTCATTCT TCTCTCCCAC ACAAGCAGTC TT - #TTTCTACA       2580                                                                          - GCCAGTAAGG CAGCTCTGTC TGGTAGCAGA TGGTCCCATT ATTCTAGGGT CT - #TACTCTTT       2640                                                                          - GTATGATGAA AAGAATGTGT TATGAATCGG TGCTGTCAGC CCTGCTGTCA GA - #CCTTCTTC       2700                                                                          - CACAGCAAAT GAGATGTATG CCCAAAGCGG TAGAATTAAA GAAGAGTAAA AT - #GGCTGTTG       2760                                                                          #        2791      AAAA AAAAAAAAAA A                                          - (2) INFORMATION FOR SEQ ID NO:134:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 467 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:134:                               -      Met Thr Glu Leu Pro Ala Pro Leu - # Ser Tyr Phe Gln Asn Ala Gln        Met                                                                           #   15                                                                        -      Ser Glu Asp Asn His Leu Ser Asn - # Thr Val Arg Ser Gln Asn Asp        Asn                                                                           #                 30                                                          -      Arg Glu Arg Gln Glu His Asn Asp - # Arg Arg Ser Leu Gly His Pro        Glu                                                                           #             45                                                              -      Pro Leu Ser Asn Gly Arg Pro Gln - # Gly Asn Ser Arg Gln Val Val        Glu                                                                           #         60                                                                  -      Gln Asp Glu Glu Glu Asp Glu Glu - # Leu Thr Leu Lys Tyr Gly Ala        Lys                                                                           #     80                                                                      -      His Val Ile Met Leu Phe Val Pro - # Val Thr Leu Cys Met Val Val        Val                                                                           #   95                                                                        -      Val Ala Thr Ile Lys Ser Val Ser - # Phe Tyr Thr Arg Lys Asp Gly        Gln                                                                           #                110                                                          -      Leu Ile Tyr Thr Pro Phe Thr Glu - # Asp Thr Glu Thr Val Gly Gln        Arg                                                                           #            125                                                              -      Ala Leu His Ser Ile Leu Asn Ala - # Ala Ile Met Ile Ser Val Ile        Val                                                                           #        140                                                                  -      Val Met Thr Ile Leu Leu Val Val - # Leu Tyr Lys Tyr Arg Cys Tyr        Lys                                                                           #    160                                                                      -      Val Ile His Ala Trp Leu Ile Ile - # Ser Ser Leu Leu Leu Leu Phe        Phe                                                                           #   175                                                                       -      Phe Ser Phe Ile Tyr Leu Gly Glu - # Val Phe Lys Thr Tyr Asn Val        Ala                                                                           #                190                                                          -      Val Asp Tyr Ile Thr Val Ala Leu - # Leu Ile Trp Asn Phe Gly Val        Val                                                                           #            205                                                              -      Gly Met Ile Ser Ile His Trp Lys - # Gly Pro Leu Arg Leu Gln Gln        Ala                                                                           #        220                                                                  -      Tyr Leu Ile Met Ile Ser Ala Leu - # Met Ala Leu Val Phe Ile Lys        Tyr                                                                           #    240                                                                      -      Leu Pro Glu Trp Thr Ala Trp Leu - # Ile Leu Ala Val Ile Ser Val        Tyr                                                                           #   255                                                                       -      Asp Leu Val Ala Val Leu Cys Pro - # Lys Gly Pro Leu Arg Met Leu        Val                                                                           #                270                                                          -      Glu Thr Ala Gln Glu Arg Asn Glu - # Thr Leu Phe Pro Ala Leu Ile        Tyr                                                                           #            285                                                              -      Ser Ser Thr Met Val Trp Leu Val - # Asn Met Ala Glu Gly Asp Pro        Glu                                                                           #        300                                                                  -      Ala Gln Arg Arg Val Ser Lys Asn - # Ser Lys Tyr Asn Ala Glu Ser        Thr                                                                           #    320                                                                      -      Glu Arg Glu Ser Gln Asp Thr Val - # Ala Glu Asn Asp Asp Gly Gly        Phe                                                                           #   335                                                                       -      Ser Glu Glu Trp Glu Ala Gln Arg - # Asp Ser His Leu Gly Pro His        Arg                                                                           #                350                                                          -      Ser Thr Pro Glu Ser Arg Ala Ala - # Val Gln Glu Leu Ser Ser Ser        Ile                                                                           #            365                                                              -      Leu Ala Gly Glu Asp Pro Glu Glu - # Arg Gly Val Lys Leu Gly Leu        Gly                                                                           #        380                                                                  -      Asp Phe Ile Phe Tyr Ser Val Leu - # Val Gly Lys Ala Ser Ala Thr        Ala                                                                           #    400                                                                      -      Ser Gly Asp Trp Asn Thr Thr Ile - # Ala Cys Phe Val Ala Ile Leu        Ile                                                                           #   415                                                                       -      Gly Leu Cys Leu Thr Leu Leu Leu - # Leu Ala Ile Phe Lys Lys Ala        Leu                                                                           #                430                                                          -      Pro Ala Leu Pro Ile Ser Ile Thr - # Phe Gly Leu Val Phe Tyr Phe        Ala                                                                           #            445                                                              -      Thr Asp Tyr Leu Val Gln Pro Phe - # Met Asp Gln Leu Ala Phe His        Gln                                                                           #        460                                                                  -      Phe Tyr Ile                                                                 465                                                                      - (2) INFORMATION FOR SEQ ID NO:135:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1962 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:135:                               - ACCAACACGG CAGCTGAGGC GGAAACCTAG GCTGCGAGCC GGCCGCCCGG GC - #GCGGAGAG         60                                                                          - AGAAGGAACC AACACAAGAC AGCAGCCCTT CGAGGTCTTT AGGCAGCTTG GA - #GGAGAACA        120                                                                          - CATGAGAGAA AGAATCCCAA GAGGTTTTGT TTTCTTTGAG AAGGTATTTC TG - #TCCAGCTG        180                                                                          - CTCCAATGAC AGAGATACCT GCACCTTTGT CCTACTTCCA GAATGCCCAG AT - #GTCTGAGG        240                                                                          - ACAGCCACTC CAGCAGCGCC ATCCGGAGCC AGAATGACAG CCAAGAACGG CA - #GCAGCAGC        300                                                                          - ATGACAGGCA GAGACTTGAC AACCCTGAGC CAATATCTAA TGGGCGGCCC CA - #GAGTAACT        360                                                                          - CAAGACAGGT GGTGGAACAA GATGAGGAGG AAGACGAAGA GCTGACATTG AA - #ATATGGAG        420                                                                          - CCAAGCATGT CATCATGCTC TTTGTCCCCG TGACCCTCTG CATGGTCGTC GT - #CGTGGCCA        480                                                                          - CCATCAAATC AGTCAGCTTC TATACCCGGA AGGACGGTCA GCTAATCTAC AC - #CCCATTCA        540                                                                          - CAGAAGACAC TGAGACTGTA GGCCAAAGAG CCCTGCACTC GATCCTGAAT GC - #GGCCATCA        600                                                                          - TGATCAGTGT CATTGTCATT ATGACCATCC TCCTGGTGGT CCTGTATAAA TA - #CAGGTGCT        660                                                                          - ACAAGGTCAT CCACGCCTGG CTTATTATTT CATCTCTGTT GTTGCTGTTC TT - #TTTTTCGT        720                                                                          - TCATTTACTT AGGGGAAGTA TTTAAGACCT ACAATGTCGC CGTGGACTAC GT - #TACAGTAG        780                                                                          - CACTCCTAAT CTGGAATTTT GGTGTGGTCG GGATGATTGC CATCCACTGG AA - #AGGCCCCC        840                                                                          - TTCGACTGCA GCAGGCGTAT CTCATTATGA TCAGTGCCCT CATGGCCCTG GT - #ATTTATCA        900                                                                          - AGTACCTCCC CGAATGGACC GCATGGCTCA TCTTGGCTGT GATTTCAGTA TA - #TGATTTGG        960                                                                          - TGGCTGTTTT ATGTCCCAAA GGCCCACTTC GTATGCTGGT TGAAACAGCT CA - #GGAAAGAA       1020                                                                          - ATGAGACTCT CTTTCCAGCT CTTATCTATT CCTCAACAAT GGTGTGGTTG GT - #GAATATGG       1080                                                                          - CTGAAGGAGA CCCAGAAGCC CAAAGGAGGG TACCCAAGAA CCCCAAGTAT AA - #CACACAAA       1140                                                                          - GAGCGGAGAG AGAGACACAG GACAGTGGTT CTGGGAACGA TGATGGTGGC TT - #CAGTGAGG       1200                                                                          - AGTGGGAGGC CCAAAGAGAC AGTCACCTGG GGCCTCATCG CTCCACTCCC GA - #GTCAAGAG       1260                                                                          - CTGCTGTCCA GGAACTTTCT GGGAGCATTC TAACGAGTGA AGACCCGGAG GA - #AAGAGGAG       1320                                                                          - TAAAACTTGG ACTGGGAGAT TTCATTTTCT ACAGTGTTCT GGTTGGTAAG GC - #CTCAGCAA       1380                                                                          - CCGCCAGTGG AGACTGGAAC ACAACCATAG CCTGCTTTGT AGCCATACTG AT - #CGGCCTGT       1440                                                                          - GCCTTACATT ACTCCTGCTC GCCATTTTCA AGAAAGCGTT GCCAGCCCTC CC - #CATCTCCA       1500                                                                          - TCACCTTCGG GCTCGTGTTC TACTTCGCCA CGGATTACCT TGTGCAGCCC TT - #CATGGACC       1560                                                                          - AACTTGCATT CCATCAGTTT TATATCTAGC CTTTCTGCAG TTAGAACATG GA - #TGTTTCTT       1620                                                                          - CTTTGATTAT CAAAAACACA AAAACAGAGA GCAAGCCCGA GGAGGAGACT GG - #TGACTTTC       1680                                                                          - CTGTGTCCTC AGCTAACAAA GGCAGGACTC CAGCTGGACT TCTGCAGCTT CC - #TTCCGAGT       1740                                                                          - CTCCCTAGCC ACCCGCACTA CTGGACTGTG GAAGGAAGCG TCTACAGAGG AA - #CGGTTTCC       1800                                                                          - AACATCCATC GCTGCAGCAG ACGGTGTCCC TCAGTGACTT GAGAGACAAG GA - #CAAGGAAA       1860                                                                          - TGTGCTGGGC CAAGGAGCTG CCGTGCTCTG CTAGCTTTGA CCGTGGGCAT GG - #AGATTTAC       1920                                                                          #1962              CTAA GGTAAACAAA GTGAGGTGAA CC                              - (2) INFORMATION FOR SEQ ID NO:136:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 2285 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:136:                               - GAATTCGGCA CGAGGGCATT TCCAGCAGTG AGGAGACAGC CAGAAGCAAG CT - #TTTGGAGC         60                                                                          - TGAAGGAACC TGAGACAGAA GCTAGTCCCC CCTCTGAATT TTACTGATGA AG - #AAACTGAG        120                                                                          - GCCACAGAGC TAAAGTGACT TTTCCCAAGG TCGCCCAGCG AGGACGTGGG AC - #TTCTCAGA        180                                                                          - CGTCAGGAGA GTGATGTGAG GGAGCTGTGT GACCATAGAA AGTGACGTGT TA - #AAAACCAG        240                                                                          - CGCTGCCCTC TTTGAAAGCC AGGGAGCATC ATTCATTTAG CCTGCTGAGA AG - #AAGAAACC        300                                                                          - AAGTGTCCGG GATTCAAGAC CTCTCTGCGG CCCCAAGTGT TCGTGGTGCT TC - #CAGAGGCA        360                                                                          - GGGCTATGCT CACATTCATG GCCTCTGACA GCGAGGAAGA AGTGTGTGAT GA - #GCGGACGT        420                                                                          - CCCTAATGTC GGCCGAGAGC CCCACGCCGC GCTCCTGCCA GGAGGGCAGG CA - #GGGCCCAG        480                                                                          - AGGATGGAGA GAATACTGCC CAGTGGAGAA GCCAGGAGAA CGAGGAGGAC GG - #TGAGGAGG        540                                                                          - ACCCTGACCG CTATGTCTGT AGTGGGGTTC CCGGGCGGCC GCCAGGCCTG GA - #GGAAGAGC        600                                                                          - TGACCCTCAA ATACGGAGCG AAGCATGTGA TCATGCTGTT TGTGCCTGTC AC - #TCTGTGCA        660                                                                          - TGATCGTGGT GGTAGCCACC ATCAAGTCTG TGCGCTTCTA CACAGAGAAG AA - #TGGACAGC        720                                                                          - TCATCTACAC GCCATTCACT GAGGACACAC CCTCGGTGGG CCAGCGCCTC CT - #CAACTCCG        780                                                                          - TGCTGAACAC CCTCATCATG ATCAGCGTCA TCGTGGTTAT GACCATCTTC TT - #GGTGGTGC        840                                                                          - TCTACAAGTA CCGCTGCTAC AAGTTCATCC ATGGCTGGTT GATCATGTCT TC - #ACTGATGC        900                                                                          - TGCTGTTCCT CTTCACCTAT ATCTACCTTG GGGAAGTGCT CAAGACCTAC AA - #TGTGGCCA        960                                                                          - TGGACTACCC CACCCTCTTG CTGACTGTCT GGAACTTCGG GGCAGTGGGC AT - #GGTGTGCA       1020                                                                          - TCCACTGGAA GGGCCCTCTG GTGCTGCAGC AGGCCTACCT CATCATGATC AG - #TGCGCTCA       1080                                                                          - TGGCCCTAGT GTTCATCAAG TACCTCCCAG AGTGGTCCGC GTGGGTCATC CT - #GGGCGCCA       1140                                                                          - TCTCTGTGTA TGATCTCGTG GCTGTGCTGT GTCCCAAAGG GCCTCTGAGA AT - #GCTGGTAG       1200                                                                          - AAACTGCCCA GGAGAGAAAT GAGCCCATAT TCCCTGCCCT GATATACTCA TC - #TGCCATGG       1260                                                                          - TGTGGACGGT TGGCATGGCG AAGCTGGACC CCTCCTCTCA GGGTGCCCTC CA - #GCTCCCCT       1320                                                                          - ACGACCCGGA GATGGAAGAA GACTCCTATG ACAGTTTTGG GGAGCCTTCA TA - #CCCCGAAG       1380                                                                          - TCTTTGAGCC TCCCTTGACT GGCTACCCAG GGGAGGAGCT GGAGGAAGAG GA - #GGAAAGGG       1440                                                                          - GCGTGAAGCT TGGCCTCGGG GACTTCATCT TCTACAGTGT GCTGGTGGGC AA - #GGCGGCTG       1500                                                                          - CCACGGGCAG CGGGGACTGG AATACCACGC TGGCCTGCTT CGTGGCCATC CT - #CATTGGCT       1560                                                                          - TGTGTCTGAC CCTCCTGCTG CTTGCTGTGT TCAAGAAGGC GCTGCCCGCC CT - #CCCCATCT       1620                                                                          - CCATCACGTT CGGGCTCATC TTTTACTTCT CCACGGACAA CCTGGTGCGG CC - #GTTCATGG       1680                                                                          - ACACCCTGGC CTCCCATCAG CTCTACATCT GAGGGACATG GTGTGCCACA GG - #CTGCAAGC       1740                                                                          - TGCAGGGAAT TTTCATTGGA TGCAGTTGTA TAGTTTTACA CTCTAGTGCC AT - #ATATTTTT       1800                                                                          - AAGACTTTTC TTTCCTTAAA AAATAAAGTA CGTGTTTACT TGGTGAGGAG GA - #GGCAGAAC       1860                                                                          - CAGCTCTTTG GTGCCAGCTG TTTCATCACC AGACTTTGGC TCCCGCTTTG GG - #GAGCGCCT       1920                                                                          - CGCTTCACGG ACAGGAAGCA CAGCAGGTTT ATCCAGATGA ACTGAGAAGG TC - #AGATTAGG       1980                                                                          - GTGGGGAGAA GAGCATCCGG CATGAGGGCT GAGATGCCCA AAGAGTGTGC TC - #GGGAGTGG       2040                                                                          - CCCCTGGCAC CTGGGTGCTC TGGCTGGAGA GGAAAAGCCA GTTCCCTACG AG - #GAGTGTTC       2100                                                                          - CCAATGCTTT GTCCATGATG TCCTTGTTAT TTTATTNCCY TTANAAACTG AN - #TCCTNTTN       2160                                                                          - TTNTTDCGGC AGTCACMCTN CTGGGRAGTG GCTTAATAGT AANATCAATA AA - #NAGNTGAG       2220                                                                          - TCCTNTTAGA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AA - #AAAAAAAA       2280                                                                          #          2285                                                               - (2) INFORMATION FOR SEQ ID NO:137:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 448 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:137:                               -      Met Leu Thr Phe Met Ala Ser Asp - # Ser Glu Glu Glu Val Cys Asp        Glu                                                                           #   15                                                                        -      Arg Thr Ser Leu Met Ser Ala Glu - # Ser Pro Thr Pro Arg Ser Cys        Gln                                                                           #                 30                                                          -      Glu Gly Arg Gln Gly Pro Glu Asp - # Gly Glu Asn Thr Ala Gln Trp        Arg                                                                           #             45                                                              -      Ser Gln Glu Asn Glu Glu Asp Gly - # Glu Glu Asp Pro Asp Arg Tyr        Val                                                                           #         60                                                                  -      Cys Ser Gly Val Pro Gly Arg Pro - # Pro Gly Leu Glu Glu Glu Leu        Thr                                                                           #     80                                                                      -      Leu Lys Tyr Gly Ala Lys His Val - # Ile Met Leu Phe Val Pro Val        Thr                                                                           #   95                                                                        -      Leu Cys Met Ile Val Val Val Ala - # Thr Ile Lys Ser Val Arg Phe        Tyr                                                                           #                110                                                          -      Thr Glu Lys Asn Gly Gln Leu Ile - # Tyr Thr Pro Phe Thr Glu Asp        Thr                                                                           #            125                                                              -      Pro Ser Val Gly Gln Arg Leu Leu - # Asn Ser Val Leu Asn Thr Leu        Ile                                                                           #        140                                                                  -      Met Ile Ser Val Ile Val Val Met - # Thr Ile Phe Leu Val Val Leu        Tyr                                                                           #    160                                                                      -      Lys Tyr Arg Cys Tyr Lys Phe Ile - # His Gly Trp Leu Ile Met Ser        Ser                                                                           #   175                                                                       -      Leu Met Leu Leu Phe Leu Phe Thr - # Tyr Ile Tyr Leu Gly Glu Val        Leu                                                                           #                190                                                          -      Lys Thr Tyr Asn Val Ala Met Asp - # Tyr Pro Thr Leu Leu Leu Thr        Val                                                                           #            205                                                              -      Trp Asn Phe Gly Ala Val Gly Met - # Val Cys Ile His Trp Lys Gly        Pro                                                                           #        220                                                                  -      Leu Val Leu Gln Gln Ala Tyr Leu - # Ile Met Ile Ser Ala Leu Met        Ala                                                                           #    240                                                                      -      Leu Val Phe Ile Lys Tyr Leu Pro - # Glu Trp Ser Ala Trp Val Ile        Leu                                                                           #   255                                                                       -      Gly Ala Ile Ser Val Tyr Asp Leu - # Val Ala Val Leu Cys Pro Lys        Gly                                                                           #                270                                                          -      Pro Leu Arg Met Leu Val Glu Thr - # Ala Gln Glu Arg Asn Glu Pro        Ile                                                                           #            285                                                              -      Phe Pro Ala Leu Ile Tyr Ser Ser - # Ala Met Val Trp Thr Val Gly        Met                                                                           #        300                                                                  -      Ala Lys Leu Asp Pro Ser Ser Gln - # Gly Ala Leu Gln Leu Pro Tyr        Asp                                                                           #    320                                                                      -      Pro Glu Met Glu Glu Asp Ser Tyr - # Asp Ser Phe Gly Glu Pro Ser        Tyr                                                                           #   335                                                                       -      Pro Glu Val Phe Glu Pro Pro Leu - # Thr Gly Tyr Pro Gly Glu Glu        Leu                                                                           #                350                                                          -      Glu Glu Glu Glu Glu Arg Gly Val - # Lys Leu Gly Leu Gly Asp Phe        Ile                                                                           #            365                                                              -      Phe Tyr Ser Val Leu Val Gly Lys - # Ala Ala Ala Thr Gly Ser Gly        Asp                                                                           #        380                                                                  -      Trp Asn Thr Thr Leu Ala Cys Phe - # Val Ala Ile Leu Ile Gly Leu        Cys                                                                           #    400                                                                      -      Leu Thr Leu Leu Leu Leu Ala Val - # Phe Lys Lys Ala Leu Pro Ala        Leu                                                                           #   415                                                                       -      Pro Ile Ser Ile Thr Phe Gly Leu - # Ile Phe Tyr Phe Ser Thr Asp        Asn                                                                           #                430                                                          -      Leu Val Arg Pro Phe Met Asp Thr - # Leu Ala Ser His Gln Leu Tyr        Ile                                                                           #            445                                                              - (2) INFORMATION FOR SEQ ID NO:138:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 372 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:138:                               -      Glu Glu Leu Thr Leu Lys Tyr Gly - # Ala Lys His Val Ile Met Leu        Phe                                                                           #   15                                                                        -      Val Pro Val Thr Leu Cys Met Ile - # Val Val Val Ala Thr Ile Lys        Ser                                                                           #                 30                                                          -      Val Arg Phe Tyr Thr Glu Lys Asn - # Gly Gln Leu Ile Tyr Thr Pro        Phe                                                                           #             45                                                              -      Thr Glu Asp Thr Pro Ser Val Gly - # Gln Arg Leu Leu Asn Ser Val        Leu                                                                           #         60                                                                  -      Asn Thr Leu Ile Met Ile Ser Val - # Ile Val Val Met Thr Ile Phe        Leu                                                                           #     80                                                                      -      Val Val Leu Tyr Lys Tyr Arg Cys - # Tyr Lys Phe Ile His Gly Trp        Leu                                                                           #   95                                                                        -      Ile Met Ser Ser Leu Met Leu Leu - # Phe Leu Phe Thr Tyr Ile Tyr        Leu                                                                           #                110                                                          -      Gly Glu Val Leu Lys Thr Tyr Asn - # Val Ala Met Asp Tyr Pro Thr        Leu                                                                           #            125                                                              -      Leu Leu Thr Val Trp Asn Phe Gly - # Ala Val Gly Met Val Cys Ile        His                                                                           #        140                                                                  -      Trp Lys Gly Pro Leu Val Leu Gln - # Gln Ala Tyr Leu Ile Met Ile        Ser                                                                           #    160                                                                      -      Ala Leu Met Ala Leu Val Phe Ile - # Lys Tyr Leu Pro Glu Trp Ser        Ala                                                                           #   175                                                                       -      Trp Val Ile Leu Gly Ala Ile Ser - # Val Tyr Asp Leu Val Ala Val        Leu                                                                           #                190                                                          -      Cys Pro Lys Gly Pro Leu Arg Met - # Leu Val Glu Thr Ala Gln Glu        Arg                                                                           #            205                                                              -      Asn Glu Pro Ile Phe Pro Ala Leu - # Ile Tyr Ser Ser Ala Met Val        Trp                                                                           #        220                                                                  -      Thr Val Gly Met Ala Lys Leu Asp - # Pro Ser Ser Gln Gly Ala Leu        Gln                                                                           #    240                                                                      -      Leu Pro Tyr Asp Pro Glu Met Glu - # Glu Asp Ser Tyr Asp Ser Phe        Gly                                                                           #   255                                                                       -      Glu Pro Ser Tyr Pro Glu Val Phe - # Glu Pro Pro Leu Thr Gly Tyr        Pro                                                                           #                270                                                          -      Gly Glu Glu Leu Glu Glu Glu Glu - # Glu Arg Gly Val Lys Leu Gly        Leu                                                                           #            285                                                              -      Gly Asp Phe Ile Phe Tyr Ser Val - # Leu Val Gly Lys Ala Ala Ala        Thr                                                                           #        300                                                                  -      Gly Ser Gly Asp Trp Asn Thr Thr - # Leu Ala Cys Phe Val Ala Ile        Leu                                                                           #    320                                                                      -      Ile Gly Leu Cys Leu Thr Leu Leu - # Leu Leu Ala Val Phe Lys Lys        Ala                                                                           #   335                                                                       -      Leu Pro Ala Leu Pro Ile Ser Ile - # Thr Phe Gly Leu Ile Phe Tyr        Phe                                                                           #                350                                                          -      Ser Thr Asp Asn Leu Val Arg Pro - # Phe Met Asp Thr Leu Ala Ser        His                                                                           #            365                                                              -      Gln Leu Tyr Ile                                                                 370                                                                  - (2) INFORMATION FOR SEQ ID NO:139:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 31 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:139:                               #          31      CAGA GGTACCTGCA C                                          - (2) INFORMATION FOR SEQ ID NO:140:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 25 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:140:                               #               25 GAAA AAGAC                                                 - (2) INFORMATION FOR SEQ ID NO:141:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 24 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:141:                               #                24GTAT GCTG                                                  - (2) INFORMATION FOR SEQ ID NO:142:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 33 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:142:                               #         33       GCTA TGGTTGTGTT CCA                                        - (2) INFORMATION FOR SEQ ID NO:143:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 19 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:143:                               # 19               GTG                                                        - (2) INFORMATION FOR SEQ ID NO:144:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 19 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:144:                               # 19               GTG                                                        - (2) INFORMATION FOR SEQ ID NO:145:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 19 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:145:                               # 19               TTA                                                        - (2) INFORMATION FOR SEQ ID NO:146:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 19 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:146:                               # 19               TTA                                                        - (2) INFORMATION FOR SEQ ID NO:147:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 19 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:147:                               # 19               GTA                                                        - (2) INFORMATION FOR SEQ ID NO:148:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 19 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:148:                               # 19               GTA                                                        - (2) INFORMATION FOR SEQ ID NO:149:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 19 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:149:                               # 19               GTA                                                        - (2) INFORMATION FOR SEQ ID NO:150:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1092 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:150:                               - GTCTAGATAA GNCAACATTC AGGGGTAGAA GGGGACTGTT TATTTTTTCC TT - #TAGTCTCT         60                                                                          - CTTAAAGAGT GAGAAAAATT TTCCCAGGAA TCCCGGTGGA CTTTGCTTCA CC - #ACTCATAG        120                                                                          - GTTCATACCA AGTTACAACC CCACAACCTT AGAGCTTTTG TTAGGAAGAG GC - #TTGGTGGG        180                                                                          - ATTACCGTGC TTGGCTTGGC TTGGTCAGGA TTCACCACCA GAGTCATGTG GG - #AGGGGGTG        240                                                                          - GGAACCCAAA CAATTCAGGA TTCTGCCCTC AGGAAATAAA GGAGAAAATA GC - #TGTTGGAT        300                                                                          - AAACTACCAG CAGGCACTGC TACAGCCCAT GCTTTGTGGT TTAAGGGCCA GC - #TAGTTACA        360                                                                          - ATGACAGCTA GTTACTGTTT CCATGTAATT TTCTTAAAGG TATTAAATTT TT - #CTAAATAT        420                                                                          - TAGAGCTGTA ACTTCCACTT TCTCTTGAAG GCACAGWAAG GGAGTCACAA GA - #CACTGTTG        480                                                                          - CAGAGAATGA TGATGGCGGG TTCAGTGAGG AATGGGAASC CCAGRGGGAC AN - #TCATCTAG        540                                                                          - GGCCTCATCG CTCTACACCT GAGTCACGAG CTKCTNTCCA GGRACTTTCC AN - #CAGTATCC        600                                                                          - TCGCTGGTGA AGACCCAGAG GAAAGNATGT TCANTTCTCC ATNTTTCAAA GT - #CATGGATT        660                                                                          - CCTTTAGGTA GCTACATTAT CAACCTTTTT GAGAATAAAA TGAATTGAGA GT - #GTTACAGT        720                                                                          - CTAATTCTAT ATCACATGTA ACTTTTATTT GGATATATCA GTAATAGTGC TT - #TTTYNTTT        780                                                                          - TTTTTTTTTT TTTTTTTTTT TTTTNGGNGA NAGAGTCTCG CTCTGTCGCC AG - #GTTGGAGT        840                                                                          - GCAATGGTGC GATCTTGGCT CACTGAAAGC TCCACCNCCC GGGTTCAAGT GA - #TTCTCCTG        900                                                                          - CCTCAGCCNC CCAAGTAGNT GGGACTACAG GGGTGCGCCA CCACGCCTGG GA - #TAATTTTG        960                                                                          - GGNTTTTTAG TAGAGATGGC GTTTCACCAN CTTGGNGCAG GCTGGTCTTG GA - #ACTCCTGA       1020                                                                          - NATCATGATC TGCCTGCCTT AGCCTCCCCA AAGTGCTGGG ATTNCAGGGG TG - #AGCCACTG       1080                                                                          #     1092                                                                    - (2) INFORMATION FOR SEQ ID NO:151:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1003 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:151:                               - CTGCAGTGAG CCGAGATCAT GCTGCTGTAC TCCAGCCTGG GCCACAGAGC CA - #AACTCCAT         60                                                                          - CTCCCAAAAA AAAAAAATAT TAATTAATAT GATNAAATGA TGCCTATCTC AG - #AATTCTTG        120                                                                          - TAAGGATTTC TTAGKACAAG TGCTGGGTAT AAACTATANA TTCRATAGAT GN - #CGATTATT        180                                                                          - ACTTAYTATT GTTATTGATA AATAACAGCA GCATCTACAG TTAAGACTCC AG - #AGTCAGTC        240                                                                          - ACATAGAATC TGGNACTCCT ATTGTAGNAA ACCCCNMMAG AAAGAAAACA CA - #GCTGAAGC        300                                                                          - CTAATTTTGT ATATCATTTA CTGACTTCTC TCATTCATTG TGGGGTTGAG TA - #GGGCAGTG        360                                                                          - ATATTTTTGA ATTGTGAAAT CATANCAAAG AGTGACCAAC TTTTTAATAT TT - #GTAACCTT        420                                                                          - TCCTTTTTAG GGGGAGTAAA ACTTGGATTG GGAGATTTCA TTTTCTACAG TG - #TTCTGGTT        480                                                                          - GGTAAAGCCT CAGCAACAGC CAGTGGAGAC TGGAACACAA CCATAGCCTG TT - #TCGTAGCC        540                                                                          - ATATTAATTG TMMSTATACA CTAATAAGAA TGTGTCAGAG CTCTTAATGT CM - #AAACTTTG        600                                                                          - ATTACACAGT CCCTTTAAGG CAGTTCTGTT TTAACCCCAG GTGGGTTAAA TA - #TTCCAGCT        660                                                                          - ATCTGAGGAG CTTTTNGATA ATTGGACCTC ACCTTAGTAG TTCTCTACCC TG - #GCCACACA        720                                                                          - TTAGAATCAC TTGGGAGCTT TTAAAACTGT AAGCTCTGCC CTGAGATATT CT - #TACTCAAT        780                                                                          - TTAATTGTGT AGTTTTTAAA ATTCCCCAGG AAATTCTGGT ATTTCTGTTT AG - #GAACCGCT        840                                                                          - GCCTCAAGCC TAGCAGCACA GATATGTAGG AAATTAGCTC TGTAAGGTTG GT - #CTTACAGG        900                                                                          - GATAAACAGA TCCTTCCTTA GTCCCTGGAC TTAATCACTG AGAGTTTGGG TG - #GTGGTTTT        960                                                                          #                 100 - #3GCATGCAG TGTTACTTAA GAC                             - (2) INFORMATION FOR SEQ ID NO:152:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1726 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:152:                               - GGATCCCTCC CCTTTTTAGA CCATACAAGG TAACTTCCGG ACGTTGCCAT GG - #CATCTGTA         60                                                                          - AACTGTCATG GTGTTGGCGG GGAGTGTCTT TTAGCATGCT AATGTATTAT AA - #TTAGCGTA        120                                                                          - TAGTGAGCAG TGAGGATAAC CAGAGGTCAC TCTCCTCACC ATCTTGGTTT TG - #GTGGGTTT        180                                                                          - TGGCCAGCTT CTTTATTGCA ACCAGTTTTA TCAGCAAGAT CTTTATGAGC TG - #TATCTTGT        240                                                                          - GCTGACTTCC TATCTCATCC CGNAACTAAG AGTACCTAAC CTCCTGCAAA TT - #GMAGNCCA        300                                                                          - GNAGGTCTTG GNCTTATTTN ACCCAGCCCC TATTCAARAT AGAGTNGYTC TT - #GGNCCAAA        360                                                                          - CGCCYCTGAC ACAAGGATTT TAAAGTCTTA TTAATTAAGG TAAGATAGKT CC - #TTGSATAT        420                                                                          - GTGGTCTGAA ATCACAGAAA GCTGAATTTG GAAAAAGGTG CTTGGASCTG CA - #GCCAGTAA        480                                                                          - ACAAGTTTTC ATGCAGGTGT CAGTATTTAA GGTACATCTC AAAGGATAAG TA - #CAATTGTG        540                                                                          - TATGTTGGGA TGAACAGAGA GAATGGAGCA ANCCAAGACC CAGGTAAAAG AG - #AGGACCTG        600                                                                          - AATGCCTTCA GTGAACAATG ATAGATAATC TAGACTTTTA AACTGCATAC TT - #CCTGTACA        660                                                                          - TTGTTTTTTC TTGCTTCAGG TTTTTAGAAC TCATAGTGAC GGGTCTGTTG TT - #AATCCCAG        720                                                                          - GTCTAACCGT TACCTTGATT CTGCTGAGAA TCTGATTTAC TGAAAATGTT TT - #TCTTGTGC        780                                                                          - TTATAGAATG ACAATAGAGA ACGGCAGGAG CACAACGACA GACGGAGCCT TG - #GCCACCCT        840                                                                          - GANCCATTAT CTAATGGACG ACCCAGGGTA ACTCCCGGCA GGTGGTGGAN CA - #AGATGAGG        900                                                                          - AAGAAGATGA GGANCTGACA TTGAAATATG NCGSCAAGCA TGTGATCATG CT - #CTTTGKCC        960                                                                          - CTGTGACTCT CTGCATGGTG GTGGTCGTGG NTACCATTAA GTCAGTCAGC TT - #TTATACCC       1020                                                                          - GGAAGGATGG GCAGCTGTAC GTATGAGTTT KGTTTTATTA TTCTCAAASC CA - #GTGTGGCT       1080                                                                          - TTTCTTTACA GCATGTCATC ATCACCTTGA AGGCCTCTNC ATTGAAGGGG CA - #TGACTTAG       1140                                                                          - CTGGAGAGCC CATCCTCTGT GATGGTCAGG AGCAGTTGAG AGANCGAGGG GT - #TATTACTT       1200                                                                          - CATGTTTTAA GTGGAGAAAA GGAACACTGC AGAAGTATGT TTCCTGTATG GT - #ATTACTGG       1260                                                                          - ATAGGGCTGA AGTTATGCTG AATTGAACAC ATAAATTCTT TTCCACCTCA GG - #GNCATTGG       1320                                                                          - GCGCCCATTG NTCTTCTGCC TAGAATATTC TTTCCTTTNC TNACTTKGGN GG - #ATTAAATT       1380                                                                          - CCTGTCATCC CCCTCCTCTT GGTGTTATAT ATAAAGTNTT GGTGCCGCAA AA - #GAAGTAGC       1440                                                                          - ACTCGAATAT AAAATTTTCC TTTTAATTCT CAGCAAGGNA AGTTACTTCT AT - #ATAGAAGG       1500                                                                          - GTGCACCCNT ACAGATGGAA CAATGGCAAG CGCACATTTG GGACAAGGGA GG - #GGAAAGGG       1560                                                                          - TTCTTATCCC TGACACACGT GGTCCCNGCT GNTGTGTNCT NCCCCCACTG AN - #TAGGGTTA       1620                                                                          - GACTGGACAG GCTTAAACTA ATTCCAATTG GNTAATTTAA AGAGAATNAT GG - #GGTGAATG       1680                                                                          #               1726GAA GAGNAGGTAG NAGGTAACTT GAATGA                          - (2) INFORMATION FOR SEQ ID NO:153:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1883 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:153:                               - CNCGTATAAA AGACCAACAT TGCCANCNAC AACCACAGGC AAGATCTTCT CC - #TACCTTCC         60                                                                          - CCCNNGGTGT AATACCAAGT ATTCNCCAAT TTGTGATAAA CTTTCATTGG AA - #AGTGACCA        120                                                                          - CCCTCCTTGG TTAATACATT GTCTGTGCCT GCTTTCACAC TACAGTAGCA CA - #GTTGAGTG        180                                                                          - TTTGCCCTGG AGACCATATG ACCCATAGAG CTTAAAATAT TCAGTCTGGC TT - #TTTACAGA        240                                                                          - GATGTTTCTG ACTTTGTTAA TAGAAAATCA ACCCAACTGG TTTAAATAAT GC - #ACATACTT        300                                                                          - TCTCTCTCAT AGAGTAGTGC AGAGGTAGNC AGTCCAGATT AGTASGGTGG CT - #TCACGTTC        360                                                                          - ATCCAAGGAC TCAATCTCCT TCTTTCTTCT TTAGCTTCTA ACCTCTAGCT TA - #CTTCAGGG        420                                                                          - TCCAGGCTGG AGCCCTASCC TTCATTTCTG ACAGTAGGAA GGAGTAGGGG AG - #AAAAGAAC        480                                                                          - ATAGGACATG TCAGCAGAAT TCTCTCCTTA GAAGTTCCAT ACACAACACA TC - #TCCCTAGA        540                                                                          - AGTCATTGCC CTTACTTGTT CTCATAGCCA TCCTAAATAT AAGGGAGTCA GA - #AGTAAAGT        600                                                                          - CTKKNTGGCT GGGAATATTG GCACCTGGAA TAAAAATGTT TTTCTGTGAA TG - #AGAAACAA        660                                                                          - GGGGAAGATG GATATGTGAC ATTATCTTAA GACAACTCCA GTTGCAATTA CT - #CTGCAGAT        720                                                                          - GAGAGGCACT AATTATAAGC CATATTACCT TTCTTCTGAC AACCACTTGT CA - #GCCCNCGT        780                                                                          - GGTTTCTGTG GCAGAATCTG GTTCYATAMC AAGTTCCTAA TAANCTGTAS CC - #NAAAAAAT        840                                                                          - TTGATGAGGT ATTATAATTA TTTCAATATA AAGCACCCAC TAGATGGAGC CA - #GTGTCTGC        900                                                                          - TTCACATGTT AAGTCCTTCT TTCCATATGT TAGACATTTT CTTTGAAGCA AT - #TTTAGAGT        960                                                                          - GTAGCTGTTT TTCTCAGGTT AAAAATTCTT AGCTAGGATT GGTGAGTTGG GG - #AAAAGTGA       1020                                                                          - CTTATAAGAT NCGAATTGAA TTAAGAAAAA GAAAATTCTG TGTTGGAGGT GG - #TAATGTGG       1080                                                                          - KTGGTGATCT YCATTAACAC TGANCTAGGG CTTTKGKGTT TGKTTTATTG TA - #GAATCTAT       1140                                                                          - ACCCCATTCA NAGAAGATAC CGAGACTGTG GGCCAGAGAG CCCTGCACTC AA - #TTCTGAAT       1200                                                                          - GCTGCCATCA TGATCAGNGT CATTGTWGTC ATGACTANNC TCCTGGTGGT TC - #WGTATAAA       1260                                                                          - TACAGGTGCT ATAAGGTGAG CATGAGACAC AGATCTTTGN TTTCCACCCT GT - #TCTTCTTA       1320                                                                          - TGGTTGGGTA TTCTTGTCAC AGTAACTTAA CTGATCTAGG AAAGAAAAAA TG - #TTTTGTCT       1380                                                                          - TCTAGAGATA AGTTAATTTT TAGTTTTCTT CCTCCTCACT GTGGAACATT CA - #AAAAATAC       1440                                                                          - AAAAAGGAAG CCAGGTGCAT GTGTAATGCC AGGCTCAGAG GCTGAGGCAG GA - #GGATCGCT       1500                                                                          - TGGGCCCAGG AGTTCACAAG CAGCTTGGGC AACGTAGCAA GACCCTGCCT CT - #ATTAAAGA       1560                                                                          - AAACAAAAAA CAAATATTGG AAGTATTTTA TATGCATGGA ATCTATATGT CA - #TGAAAAAA       1620                                                                          - TTAGTGTAAA ATATATATAT TATGATTAGN TATCAAGATT TAGTGATAAT TT - #ATGTTATT       1680                                                                          - TTGGGATTTC AATGCCTTTT TAGGCCATTG TCTCAAMAAA TAAAAGCAGA AA - #ACAAAAAA       1740                                                                          - AGTTGTAACT GAAAAATAAA CATTTCCATA TAATAGCACA ATCTAAGTGG GT - #TTTTGNTT       1800                                                                          - GTTTGTTTGN TTGTTGAAGC AGGGCCTTGC CCTNYCACCC AGGNTGGAGT GA - #AGTGCAGT       1860                                                                          #              1883ACTG CAG                                                   - (2) INFORMATION FOR SEQ ID NO:154:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1990 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:154:                               - ATGTTTGACA ATTTCTCCGT TCCACCCTTG ATTAAATAAG GTAGTATTCA TT - #TTTTAAGT         60                                                                          - TTTAGCTTTT GGATATATGT GTAAGTGTGG TATGCTGTCT AATGAATTAA GA - #CAATTGGT        120                                                                          - NCTKTCTTTA CCCMACANCT GGACMAAGAG CAGGCAAGAT NCAANAATCA AG - #TGACCCAG        180                                                                          - NCAAACCAGA CACATTTTCT GCTCTCAGCT AGCTTGCCAC CTAGAAAGAC TG - #GTTGTCNA        240                                                                          - AGTTGGAGTC CAAGAATCGC GGAGGATGTT TAAAATGCAG TTTCTCAGGT TC - #TCNCCACC        300                                                                          - CACCAGAAGT TTTGATTCAT TGAGTGGTGG GAGAGGGCAG AGATATTTGC GA - #TTTTAACA        360                                                                          - GCATTCTCTT GATTGTGATG CAGCTGGTTC SCAAATAGGT ACCCTAAAGA AA - #TGACAGGT        420                                                                          - GTTAAATTTA GGATGGCCAT CGCTTGTATG CCGGGAGAAG CACACGCTGG GC - #CCAATTTA        480                                                                          - TATAGGGGCT TTCGTCCTCA GCTCGAGCAR CCTCAGAACC CCGACAACCY AC - #GCCAGCKC        540                                                                          - TCTGGGCGGA TTCCRTCAGK TGGGGAAGSC CAGGTGGAGC TCTGGKTTCT CC - #CCGCAATC        600                                                                          - GTTTCTCCAG GCCGGAGGCC CCGCCCCCTT CCTCCTGGCT CCTCCCCTCC TC - #CGTGGGCC        660                                                                          - GNCCGCCAAC GACGCCAGAG CCGGAAATGA CGACAACGGT GAGGGTTCTC GG - #GCGGGGCC        720                                                                          - TGGGACAGGC AGCTCCGGGG TCCNCGNNWT NACATCGGAA ACAAAACAGC GG - #CTGGTCTG        780                                                                          - GAAGGAACCT GAKCTACGAC CCGCGGCGGC AGCGGGGCGG CGGGGAAGCG TA - #TGTGCGTG        840                                                                          - ATGGGGAGTC CGGGCAAGCC AGGAAGGCAC CGCGGACATG GGCGGCCGCG GG - #CAGGGNCC        900                                                                          - GGNCCTTTGT GGCCGCCCGG GCCGCGAAGC CGGTGTCCTA AAAGATGAGG GG - #CGGGGCGC        960                                                                          - GGCCGGTTGG GGCTGGGGAA CCCCGTGTGG GAAACCAGGA GGGGCGGCCC GT - #TTCTCGGG       1020                                                                          - CTTCGGGCGC GGCCGGGTGG AGAGAGATTC CGGGGAGCCT TGGTCCGGAA AT - #GCTGTTTG       1080                                                                          - CTCGAAGACG TCTCAGGGCG CAGGTGCCTT GGGCCGGGAT TAGTAGCCGT CT - #GAACTGGA       1140                                                                          - GTGGAGTAGG AGAAAGAGGA AGCGTCTTGG GCTGGGTCTG CTTGAGCAAC TG - #GTGAAACT       1200                                                                          - CCGCGCCTCA CGCCCCGGGT GTGTCCTTGT CCAGGGGCGA CGAGCATTCT GG - #GCGAAGTC       1260                                                                          - CGCACGCCTC TTGTTCGAGG CGGAAGACGG GGTCTTGATG CTTTCTCCTT GG - #TCGGGACT       1320                                                                          - GTCTCGAGGC ATGCATGTCC AGTGACTCTT GTGTTTGCTG CTGCTTCCCT CT - #CAGATTCT       1380                                                                          - TCTCACCGTT GTGGTCAGCT CTGCTTTAGG CATATTAATC CATAGTGGAG GC - #TGGGATGG       1440                                                                          - GTGAGAGAAT TGAGGTGACT TTTCCATAAT TCAGGTGAGA TGTGATTAGA GT - #YCGGATCC       1500                                                                          - TNCGGTGGTG GCAGAGGCTT ACCAAGAAAC ACTAACGGGA CATGGGAACC AA - #TTGAGGAT       1560                                                                          - CCAGGGAATA AAGTGTGAAG TTGACTAGGA GGTTTTCAGT TTAAGAACAT GG - #CAGAGACA       1620                                                                          - TTCTCAGAAA TAAGGAAGTT AGGAAGAAAG ACCTGGTTTA GAGAGGAGGG CG - #AGGAAGTG       1680                                                                          - GTTTGGAAGT GTCACTTTGG AAGTGCCAGC AGGTGAAAAT GCCCTGTGAA CA - #GGACTGGA       1740                                                                          - GCTGAAAACA GGAATCAATT CCATAGATTT CCAGTTGATG TTGGAGCAGT GG - #AGAAGTCT       1800                                                                          - AANCTAAGGA AGGGGAAGAG GAGGCCAAGC CAAACACTTA GGAACACTTN CN - #ACGAGGGG       1860                                                                          - GTGGAAGAAG AGCAAGGAGC CAGCTGAGGA GAATGAGTGT GGTTGGAGAA CC - #ACCACAGC       1920                                                                          - NCAGGGTCGC CAGANCTGAG GAAGGGGAGG GAAGCTTATC GAGKAMSGWC RA - #CMKCGAGT       1980                                                                          #      1990                                                                   - (2) INFORMATION FOR SEQ ID NO:155:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 736 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:155:                               - GTCTTTCCCA TCTTCTCCAC AGAGTTTGTG CCTTACATTA TTACTCCTTG CC - #ATTTTCAA         60                                                                          - GAAAGCATTG TCAGCTCTTC CAATCTCCAT CACCTTTGGG CTTGTTTTCT AC - #TTTGCCAC        120                                                                          - AGATTATCTT GTACAGCCTT TTATGGACCA ATTAGCATTC CATCAATTTT AT - #ATCTAGCA        180                                                                          - TATTTGCGGT TAGAATCCCA TGGATGTTTC TTCTTTGACT ATAACAAAAT CT - #GGGGAGGA        240                                                                          - CAAAGGTGAT TTCCTGTGTC CACATCTAAC AAATCAAGAT CCCCGGCTGG AC - #TTTTGGAG        300                                                                          - GTTCCTTCCA AGTCTTCCTG ACCACCTTGC ACTATTGGAC TTTGGAAGGA GG - #TGCCTATA        360                                                                          - GAAAACGATT TTGAACATAC TTCATCGCAG TGGACTGTGT CCTCGGTGCA GA - #AACTACCA        420                                                                          - GATTTGAGGG ACGAGGTCAA GGAGATATGA TAGGCCCGGA AGTTGCTGTG CC - #CCATCAGC        480                                                                          - AGCTTGACGC GTGGTCACAG GACGATTTTC ACTGACACTG CGAACTCTCA GG - #ACTACCGT        540                                                                          - TACCAAGAGG TTAGGTGAAG TGGTTTAAAC CAAACGGAAC TCTTCATCTT AA - #ACTACACG        600                                                                          - TTGAAAATCA ACCCAATAAT TCTGTATTAA CTGAATTCTG AACTTTTCAG GA - #GGTACTGT        660                                                                          - GAGGAAGAGC AGGCACCACC AGCAGAATGG GGAATGGAGA GGTGGGCAGG GG - #TTCCAGCT        720                                                                          #   736                                                                       - (2) INFORMATION FOR SEQ ID NO:156:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1117 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:156:                               - GGATCCGCCC GCCTTGGCCT CCCAAAGTGC TGGGATTACA GGCATGAGCC AC - #CGCTCCTG         60                                                                          - GCTGAGTCTG CGATTTCTTG CCAGCTCTAC CCAGTTGTGT CATCTTAAGC AA - #GTCACTGA        120                                                                          - ACTTCTCTGG ATTCCCTTCT CCTNNWGTAA AATAAGNATG TTATCTGNCC NN - #CCTGCCTT        180                                                                          - GGGCATTGTG ATAAGGATAA GATGACATTA TAGAATNTNG CAAAATTAAA AG - #CGCTAGAC        240                                                                          - AAATGATTTT ATGAAAATAT AAAGATTAGN TTGAGTTTGG GCCAGCATAG AA - #AAAGGAAT        300                                                                          - GTTGAGAACA TTCCNTTAAG GATTACTCAA GCYCCCCTTT TGSTGKNWAA TC - #AGANNGTC        360                                                                          - ATNNAMNTAT CNTNTGTGGG YTGAAAATGT TTGGTTGTCT CAGGCGGTTC CT - #ACTTATTG        420                                                                          - CTAAAGAGTC CTACCTTGAG CTTATAGTAA ATTTGTCAGT TAGTTGAAAG TC - #GTGACAAA        480                                                                          - TTAATACATT CCTGGTTTAC AAATTGGTCT TATAAGTATT TGATTGGTNT AA - #ATGNATTT        540                                                                          - ACTAGGATTT AACTAACAAT GGATGACCTG GTGAAATCCT ATTTCAGACC TA - #ATCTGGGA        600                                                                          - GCCTGCAAGT GACAACAGCC TTTGCGGTCC TTAGACAGCT TGGCCTGGAG GA - #GAACACAT        660                                                                          - GAAAGAMMGG TTTGWNTCTG NTTAWTGTAA TCTATGRAAG TGTTTTTWAT MA - #CAGTATAA        720                                                                          - TTGTMTGMAC AAAGTTCTGT TTTTCTTTCC CTTTNCAGAA CCTCAAGAGG CT - #TTGTTTTC        780                                                                          - TGTGAAACAG TATTTCTATA CAGNTGCTCC AATGACAGAG TNACCTGCAC CG - #TTGTCCTA        840                                                                          - CTTCCAGAAT GCACAGATGT CTGAGGACAA CCACCTGAGC AATACTGTAC GT - #AGCCAGGT        900                                                                          - ACAGCGTCAG TYTCTNAAAC TGCCTYYGNC AGACTGGATT CACTTATCAT CT - #CCCCTCAC        960                                                                          - CTCTGAGAAA TGCTGAGGGG GSTAGGNAGG GCTTTCTCTA CTTNACCACA TT - #TNATAATT       1020                                                                          - ATTTTTGGGT GACCTTCAGC TGATCGCTGG GAGGGACACA GGGCTTNTTT AA - #CACATAGG       1080                                                                          #    1117          CTCC CTAATTCACA TTTCANC                                    - (2) INFORMATION FOR SEQ ID NO:157:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 540 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:157:                               - CTGCAGCTTT CCTTTAAACT AGGAAGACTT GTTCCTATAC CCCAGTAACG AT - #ACACTGTA         60                                                                          - CACTAAGCAA ATAGCAGTCA AACCCAAATG AAATTTNTAC AGATGTTCTG TG - #TCATTTTA        120                                                                          - TNTTGTTTAT GTTGTCTCCC CCACCCCCAC CAGTTCACCT GCCATTTATT TC - #ATATTCAT        180                                                                          - TCAACGTCTN NNTGTGTAAA AAGAGACAAA AAACATTAAA CTTTTTTCCT TC - #GTTAATTC        240                                                                          - CTCCCTACCA CCCATTTACA AGTTTAGCCC ATACATTTTA TTAGATGTCT TT - #TATGTTTT        300                                                                          - TCTTTTNCTA GATTTAGTGG CTGTTTNGTG TCCGAAAGGT CCACTTCGTA TG - #CTGGTTGA        360                                                                          - AACAGCTCAG GAGAGAAATG AAACGCTTTT TCCAGCTCTC ATTTACTCCT GT - #AAGTATTT        420                                                                          - GGAGAATGAT ATTGAATTAG TAATCAGNGT AGAATTTATC GGGAACTTGA AG - #ANATGTNA        480                                                                          - CTATGGCAAT TTCANGGNAC TTGTCTCATC TTAAATGANA GNATCCCTGG AC - #TCCTGNAG        540                                                                          - (2) INFORMATION FOR SEQ ID NO:158:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 509 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:158:                               - CCCCGTCNAT GCATACTTTG TGTGTCCAGT GCTTACCTGG AATCCNGTCT TT - #CCCAACAG         60                                                                          - CAACAATGGT GTGGTTGGTG AATATGGCAG AAGGAGACCC GGAAGCTCAA AG - #GAGAGTAT        120                                                                          - CCAAAAATTC CAAGTATAAT GCAGAAAGTA GGTAACTYYY NTTAGATAMN AT - #CTTGATTT        180                                                                          - TNCAGGGTCA CTGTTATAAG CTAACAGTAT AGNAATGTTT TTATCGTCTT TC - #TNKGGNCA        240                                                                          - TAGACTCCTN KGAGAATCTC TTGAGAACTA TGATAATGCC CAGTAAATAC NC - #AGATAAGT        300                                                                          - ATTTAAGGAG TNCAGATACT CAAANCCCAA CAATACNGTC AAAGCATCCT AG - #GTTAAGAC        360                                                                          - AMCNCCCATT AAATACAGAA TACCAGCATG GAAAGGTTCA GGCTGAGGTT AT - #GATTGGGT        420                                                                          - TTGGGTTTTG GGNNNGTTTT TTATAAGTCA TGATTTTAAA AAGAAAAAAT AA - #ACTCTCTC        480                                                                          #           509    AGAA TCTCCTAAA                                             - (2) INFORMATION FOR SEQ ID NO:159:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 823 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:159:                               - CAGGAGTGGA CTAGGTAAAT GNAAGNTGTT TTAAAGAGAG ATGNGGNCNG GG - #ACATAGTG         60                                                                          - GTACACANCT GTAATGCTCA NCACTKATGG GGAGTACTGA AGGNGGNSGG AT - #CACTTGNG        120                                                                          - GGTCNGGAAT NTGAGANCAG CCTGGGCAAN ATGGCGAAAC CCTGTCTCTA CT - #AAAAATAG        180                                                                          - CCANAAWNWA GCCTAGCGTG GTGGCGCRCA CGCGTGGTTC CACCTACTCA GG - #AGGCNTAA        240                                                                          - GCACGAGNAN TNCTTGAACC CAGGAGGCAG AGGNTGTGGT GARCTGAGAT CG - #TGCCACTG        300                                                                          - CACTCCAGTC TGGGCGACMA AGTGAGACCC TGTCTCCNNN AAGAAAAAAA AA - #ATCTGTAC        360                                                                          - TTTTTAAGGG TTGTGGGACC TGTTAATTAT ATTGAAATGC TTCTYTTCTA GG - #TCATCCAT        420                                                                          - GCCTGGCTTA TTATATCATC TCTATTGTTG CTGCTCTTTT TTACATTCAT TT - #ACTTGGGG        480                                                                          - TAAGTTGTGA AATTTGGGGT CTGTCTTTCA GAATTAACTA CCTNNGTGCT GT - #GTAGCTAT        540                                                                          - CATTTAAAGC CATGTACTTT GNTGATGAAT TACTCTGAAG TTTTAATTGT NT - #CCACATAT        600                                                                          - AGGTCATACT TGGTATATAA AAGACTAGNC AGTATTACTA ATTGAGACAT TC - #TTCTGTNG        660                                                                          - CTCCTNGCTT ATAATAAGTA GAACTGAAAG NAACTTAAGA CTACAGTTAA TT - #CTAAGCCT        720                                                                          - TTGGGGAAGG ATTATATAGC CTTCTAGTAG GAAGTCTTGT GCNATCAGAA TG - #TTTNTAAA        780                                                                          #823               ATNG TATAAANACC AAAAATAATT GAT                             - (2) INFORMATION FOR SEQ ID NO:160:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 945 base                                                          (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:160:                               - GTTNTCCNAA CCAACTTAGG AGNTTGGACC TGGGRAAGAC CNACNTGATC TC - #CGGGAGGN         60                                                                          - AAAGACTNCA GTTGAGCCGT GATTGCACCC ACTTTACTCC AAGCCTGGGC AA - #CCAAAATG        120                                                                          - AGACACTGGC TCCAAACACA AAAACAAAAA CAAAAAAAGA GTAAATTAAT TT - #ANAGGGAA        180                                                                          - GNATTAAATA AATAATAGCA CAGTTGATAT AGGTTATGGT AAAATTATAA AG - #GTGGGANA        240                                                                          - TTAATATCTA ATGTTTGGGA GCCATCACAT TATTCTAAAT AATGTTTTGG TG - #GAAATTAT        300                                                                          - TGTACATCTT TTAAAATCTG TGTAATTTTT TTTCAGGGAA GTGTTTAAAA CC - #TATAACGT        360                                                                          - TGCTGTGGAC TACATTACTG TTNCACTCCT GATCTGGAAT TTTGGTGTGG TG - #GGAATGAT        420                                                                          - TTCCATTCAC TGGAAAGGTC CACTTCGACT CCAGCAGGCA TATCTCATTA TG - #ATTAGTGC        480                                                                          - CCTCATGNCC CTGKTGTTTA TCAAGTACCT CCCTGAATGG ACTGNGTGGC TC - #ATCTTGGC        540                                                                          - TGTGATTTCA GTATATGGTA AAACCCAAGA CTGATAATTT GTTTGTCACA GG - #AATGCCCC        600                                                                          - ACTGGAGTGT TTTCTTTCCT CATCTCTTTA TCTTGATTTA GAGAAAATGG TA - #ACGTGTAC        660                                                                          - ATCCCATAAC TCTTCAGTAA ATCATTAATT AGCTATAGTA ACTTTTTCAT TT - #GAAGATTT        720                                                                          - CGGCTGGGCA TGGTAGCTCA TGCCTGTAAT CTTAGCACTT TGGGAGGCTG AG - #GCGGGCAG        780                                                                          - ATCACCTAAG CCCAGAGTTC AAGACCAGCC TGGGCAACAT GGCAAAACCT CG - #TATCTACA        840                                                                          - GAAAATACAA AAATTAGCCG GGCATGGTGG TGCACACCTG TAGTTCCAGC TA - #CTTAGGAG        900                                                                          #                 945AT TGATCCCAGG AGGTCAAGNC TGCAG                           - (2) INFORMATION FOR SEQ ID NO:161:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 18 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:161:                               #  18              CA                                                         - (2) INFORMATION FOR SEQ ID NO:162:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 20 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:162:                               # 20               TAGA                                                       - (2) INFORMATION FOR SEQ ID NO:163:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 17 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:163:                               #   17             G                                                          - (2) INFORMATION FOR SEQ ID NO:164:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 17 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:164:                               #   17             G                                                          - (2) INFORMATION FOR SEQ ID NO:165:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 1895 base                                                         (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: cDNA                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:165:                               - TATATGAGTC GCTTTAAAAC AAAAGAAAGT TTTTACCAGC TACATTCCTT TG - #GTTTCCTT         60                                                                          - AACTAAATCC CATCACACAA CTACGGCTTC GCAGGGGGAG GCGTCCAGCG CT - #ACGGAGGC        120                                                                          - GAACGAACGC ACACCACTGA TGGCTGCTGT CAATCTCCAG GCTTCGTGCT CC - #TCCGGGCT        180                                                                          - CGCCTCTGAG GATGACGCCA ATGTGGGCAG CCAGATAGGC GCGGCGGAGC GT - #TTGGAACG        240                                                                          - ACCTCCAAGG CGGCAACAGC AGCGGAACAA CTACGGCTCC AGCAATCAGG AT - #CAACCGGA        300                                                                          - TGCTGCCATA CTTGCTGTGC CCAATGTGGT GATGCGTGAA CCTTGTGGCT CG - #CGCCCTTC        360                                                                          - AAGACTGACC GGTGGAGGAG GCGGCAGTGG TGGTCCGCCC ACAAATGAAA TG - #GAGGAAGA        420                                                                          - GCAGGGCCTG AAATACGGGG CCCAGCATGT GATCAAGTTA TTCGTCCCCG TC - #TCCCTTTG        480                                                                          - CATGCTGGTA GTGGTGGCTA CCATCAACTC CATCAGCTTC TACAACAGCA CG - #GATGTCTA        540                                                                          - TCTCCTCTAC ACACCTTTCC ATGAACAATC GCCCGAGCCT AGTGTTAAGT TC - #TGGAGTGC        600                                                                          - CTTGGCGAAC TCCCTGATCC TGATGAGCGT GGTGGTGGTG ATGACCTTTT TG - #CTGATTGT        660                                                                          - TTTGTACAAG AAGCGTTGCT ATCGCATCAT TCACGGCTGG CTGATTCTCT CC - #TCCTTCAT        720                                                                          - GTTGTTGTTC ATTTTTACGT ACTTATATTT GGAAGAGCTT CTTCGCGCCT AT - #AACATACC        780                                                                          - GATGGACTAC CCTACTGCAC TACTGATTAT GTGGAACTTT GGAGTGGTCG GA - #ATGATGTC        840                                                                          - CATCCATTGG CAGGGACCTC TGCGGTTGCA GCAAGGATAT CTCATTTTCG TG - #GCAGCCTT        900                                                                          - GATGGCCTTG GTGTTCATTA AATACCTGCC TGAATGGACT GCCTGGGCTG TA - #TTGGCTGC        960                                                                          - CATTTCTATT TGGGATCTTA TTGCTGTCCT TTCGCCAAGA GGACCCCTCC GC - #ATTCTGGT       1020                                                                          - GGAAACGGCT CAGGAGCGAA ATGAGCAAAT CTTCCCCGCT CTGATTTATT CA - #TCCACTGT       1080                                                                          - CGTTTACGCA CTTGTAAACA CTGTTACGCC GCAGCAATCG CAGGCCACAG CT - #TCCTCCTC       1140                                                                          - GCCGTCGTCC AGCAACTCCA CCACAACCAC GAGGGCCACG CAGAACTCGC TG - #GCTTCGCC       1200                                                                          - AGAGGCAGCA GCGGCTAGTG GCCAACGCAC AGGTAACTCC CATCCTCGAC AG - #AATCAGCG       1260                                                                          - GGATGACGGC AGTGTACTGG CAACTGAAGG TATGCCACTT GTGACTTTTA AA - #AGCAATTT       1320                                                                          - GCGCGGAAAC GCTGAGGCTG CGGGTTTCAC GCAAGAGTGG TCAGCTAACT TG - #AGCGAACG       1380                                                                          - TGTGGCTCGT CGCCAGATTG AAGTTCAAAG TACTCAGAGT GGAAACGCTC AG - #CGCTCCAA       1440                                                                          - CGAGTATAGG ACAGTAACAG CTCCGGATCA GAATCATCCG GATGGGCAAG AA - #GAACGTGG       1500                                                                          - CATAAAGCTT GGCCTCGGCG ACTTCATCTT CTACTCGGTA TTAGTGGGCA AG - #GCCTCCAG       1560                                                                          - CTACGGCGAC TGGACGACCA CAATCGCTTG CTTTGTGGCC ATCCTCATTG GA - #CTCTGCCT       1620                                                                          - CACTCTTCTG CTTCTGGCCA TTTGGCGCAA GGCGCTACCC GCCCTGCCCA TC - #TCAATAAC       1680                                                                          - GTTCGGATTG ATATTTTGCT TCGCCACTAG TGCGGTGGTC AAGCCGTTCA TG - #GAGGATCT       1740                                                                          - ATCGGCCAAG CAGGTGTTTA TATAAACTTG AAAAGACAAG GACACATCAA GT - #GTCTTACA       1800                                                                          - GTATCATAGT CTAACAAAGC TTTTTGTAAT CCAATTCTTT ATTTAACCAA AT - #GCATAGTA       1860                                                                          #     1895         AAAA AAAAAAAAAA AAAAA                                      - (2) INFORMATION FOR SEQ ID NO:166:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 541 amino                                                         (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: protein                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:166:                               -      Met Ala Ala Val Asn Leu Gln Ala - # Ser Cys Ser Ser Gly Leu Ala        Ser                                                                           #   15                                                                        -      Glu Asp Asp Ala Asn Val Gly Ser - # Gln Ile Gly Ala Ala Glu Arg        Leu                                                                           #                 30                                                          -      Glu Arg Pro Pro Arg Arg Gln Gln - # Gln Arg Asn Asn Tyr Gly Ser        Ser                                                                           #             45                                                              -      Asn Gln Asp Gln Pro Asp Ala Ala - # Ile Leu Ala Val Pro Asn Val        Val                                                                           #         60                                                                  -      Met Arg Glu Pro Cys Gly Ser Arg - # Pro Ser Arg Leu Thr Gly Gly        Gly                                                                           #     80                                                                      -      Gly Gly Ser Gly Gly Pro Pro Thr - # Asn Glu Met Glu Glu Glu Gln        Gly                                                                           #   95                                                                        -      Leu Lys Tyr Gly Ala Gln His Val - # Ile Lys Leu Phe Val Pro Val        Ser                                                                           #                110                                                          -      Leu Cys Met Leu Val Val Val Ala - # Thr Ile Asn Ser Ile Ser Phe        Tyr                                                                           #            125                                                              -      Asn Ser Thr Asp Val Tyr Leu Leu - # Tyr Thr Pro Phe His Glu Gln        Ser                                                                           #        140                                                                  -      Pro Glu Pro Ser Val Lys Phe Trp - # Ser Ala Leu Ala Asn Ser Leu        Ile                                                                           #    160                                                                      -      Leu Met Ser Val Val Val Val Met - # Thr Phe Leu Leu Ile Val Leu        Tyr                                                                           #   175                                                                       -      Lys Lys Arg Cys Tyr Arg Ile Ile - # His Gly Trp Leu Ile Leu Ser        Ser                                                                           #                190                                                          -      Phe Met Leu Leu Phe Ile Phe Thr - # Tyr Leu Tyr Leu Glu Glu Leu        Leu                                                                           #            205                                                              -      Arg Ala Tyr Asn Ile Pro Met Asp - # Tyr Pro Thr Ala Leu Leu Ile        Met                                                                           #        220                                                                  -      Trp Asn Phe Gly Val Val Gly Met - # Met Ser Ile His Trp Gln Gly        Pro                                                                           #    240                                                                      -      Leu Arg Leu Gln Gln Gly Tyr Leu - # Ile Phe Val Ala Ala Leu Met        Ala                                                                           #   255                                                                       -      Leu Val Phe Ile Lys Tyr Leu Pro - # Glu Trp Thr Ala Trp Ala Val        Leu                                                                           #                270                                                          -      Ala Ala Ile Ser Ile Trp Asp Leu - # Ile Ala Val Leu Ser Pro Arg        Gly                                                                           #            285                                                              -      Pro Leu Arg Ile Leu Val Glu Thr - # Ala Gln Glu Arg Asn Glu Gln        Ile                                                                           #        300                                                                  -      Phe Pro Ala Leu Ile Tyr Ser Ser - # Thr Val Val Tyr Ala Leu Val        Asn                                                                           #    320                                                                      -      Thr Val Thr Pro Gln Gln Ser Gln - # Ala Thr Ala Ser Ser Ser Pro        Ser                                                                           #   335                                                                       -      Ser Ser Asn Ser Thr Thr Thr Thr - # Arg Ala Thr Gln Asn Ser Leu        Ala                                                                           #                350                                                          -      Ser Pro Glu Ala Ala Ala Ala Ser - # Gly Gln Arg Thr Gly Asn Ser        His                                                                           #            365                                                              -      Pro Arg Gln Asn Gln Arg Asp Asp - # Gly Ser Val Leu Ala Thr Glu        Gly                                                                           #        380                                                                  -      Met Pro Leu Val Thr Phe Lys Ser - # Asn Leu Arg Gly Asn Ala Glu        Ala                                                                           #    400                                                                      -      Ala Gly Phe Thr Gln Glu Trp Ser - # Ala Asn Leu Ser Glu Arg Val        Ala                                                                           #   415                                                                       -      Arg Arg Gln Ile Glu Val Gln Ser - # Thr Gln Ser Gly Asn Ala Gln        Arg                                                                           #                430                                                          -      Ser Asn Glu Tyr Arg Thr Val Thr - # Ala Pro Asp Gln Asn His Pro        Asp                                                                           #            445                                                              -      Gly Gln Glu Glu Arg Gly Ile Lys - # Leu Gly Leu Gly Asp Phe Ile        Phe                                                                           #        460                                                                  -      Tyr Ser Val Leu Val Gly Lys Ala - # Ser Ser Tyr Gly Asp Trp Thr        Thr                                                                           #    480                                                                      -      Thr Ile Ala Cys Phe Val Ala Ile - # Leu Ile Gly Leu Cys Leu Thr        Leu                                                                           #   495                                                                       -      Leu Leu Leu Ala Ile Trp Arg Lys - # Ala Leu Pro Ala Leu Pro Ile        Ser                                                                           #                510                                                          -      Ile Thr Phe Gly Leu Ile Phe Cys - # Phe Ala Thr Ser Ala Val Val        Lys                                                                           #            525                                                              -      Pro Phe Met Glu Asp Leu Ser Ala - # Lys Gln Val Phe Ile                #        540                                                                  - (2) INFORMATION FOR SEQ ID NO:167:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:167:                               - Asn Asp Asn Arg Glu Arg Gln Glu His Asn As - #p Arg Arg Ser Leu             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:168:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:168:                               - Lys Asp Gly Gln Leu Ile Tyr Thr Pro Phe Th - #r Glu Asp Thr Glu             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:169:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:169:                               - Glu Ala Gln Arg Arg Val Ser Lys Asn Ser Ly - #s Tyr Asn Ala Glu             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:170:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:170:                               - Ser His Leu Gly Pro His Arg Ser Thr Pro Gl - #u Ser Arg Ala Ala             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:171:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 19 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:171:                               # 19               TAC                                                        - (2) INFORMATION FOR SEQ ID NO:172:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 19 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:172:                               # 19               CAT                                                        - (2) INFORMATION FOR SEQ ID NO:173:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 20 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:173:                               # 20               AGTA                                                       - (2) INFORMATION FOR SEQ ID NO:174:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 18 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:174:                               #  18              TC                                                         - (2) INFORMATION FOR SEQ ID NO:175:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 19 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:175:                               # 19               ACC                                                        - (2) INFORMATION FOR SEQ ID NO:176:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 18 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:176:                               #  18              GA                                                         - (2) INFORMATION FOR SEQ ID NO:177:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 18 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:177:                               #  18              CT                                                         - (2) INFORMATION FOR SEQ ID NO:178:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 18 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:178:                               #  18              TA                                                         - (2) INFORMATION FOR SEQ ID NO:179:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 16 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:179:                               #    16                                                                       - (2) INFORMATION FOR SEQ ID NO:180:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 18 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:180:                               #  18              CA                                                         - (2) INFORMATION FOR SEQ ID NO:181:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 27 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:181:                               #             27   AGTA TAATCCC                                               - (2) INFORMATION FOR SEQ ID NO:182:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 27 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: other nucleic acid                                  #= "primer"A) DESCRIPTION: /desc                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:182:                               #             27   AGTA TAATCCC                                               - (2) INFORMATION FOR SEQ ID NO:183:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:183:                               - Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu As - #n                             #                10                                                           __________________________________________________________________________

What is claimed is:
 1. A substantially pure mammalian presenilin-1protein.
 2. The protein of claim 1, which is a human presenilin-1protein.
 3. The protein of claim 2, comprising an amino acid sequencedefined in SEQ ID NO:2.
 4. The protein of claim 2, which is a splicevariant of a protein having an amino acid sequence defined in SEQ IDNO:2.
 5. The protein of claim 2, comprising the amino acid sequencedefined in SEQ ID NO:134.
 6. The protein of claim 1, which is a mousepresenilin-1 protein.
 7. The protein of claim 6, comprising the aminoacid sequence defined in SEQ ID NO:4.
 8. A substantially pure mammalianpresenilin-1 protein encoded by DNA which maps to chromosome 14q24.3. 9.A presenilin-1 protein that is at least 85% identical to the amino acidsequence depicted in SEQ ID NO:2 or SEQ ID NO:4 and retains normalpresenilin-1 like activity.
 10. A presenilin-1 protein that is at least85% identical to the amino acid sequence depicted in SEQ ID NO:2 or SEQID NO:4, said protein having amino acid substitutions at positionsMet146, His163, Leu171, Ala246, Ala260, Ala285, Leu286, Leu392, and/orCys410 and expression of said protein having activity that is associatedwith Alzheimer's disease.
 11. The mutant presenilin-1 protein of claim10, in which the Met residue at position 146 of SEQ ID NO:2 or SEQ IDNO:4 is substituted by Leu.
 12. The mutant presenilin-1 protein of claim10, in which the His residue at position 163 of SEQ ID NO:2 or SEQ IDNO:4 is substituted by Arg.
 13. The mutant presenilin-1 protein of claim10, in which the Leu residue at position 171 of SEQ ID NO:2 or SEQ IDNO:4 is substituted by Pro.
 14. The mutant presenilin-1 protein of claim10, in which the Ala residue at position 246 of SEQ ID NO:2 or SEQ IDNO:4 is substituted by Glu.
 15. The mutant presenilin-1 protein of claim10, in which the Ala residue at position 260 of SEQ ID NO:2 or SEQ IDNO:4 is substituted by Val.
 16. The mutant presenilin-1 protein of claim10, in which the Ala residue at position 285 of SEQ ID NO:2 or SEQ IDNO:4 is substituted by Val.
 17. The mutant presenilin-1 protein of claim10, in which the Leu residue at position 286 of SEQ ID NO:2 or SEQ IDNO:4 is substituted by Val.
 18. The mutant presenilin-1 protein of claim10, in which the Leu residue at position 392 of SEQ ID NO:2 or SEQ IDNO:4 is substituted by Val.
 19. The mutant presenilin-1 protein of claim10, in which the Cys residue at position 410 of SEQ ID NO:2 or SEQ IDNO:4 is substituted by Tyr.
 20. A presenilin-1 protein depicted in SEQID NO:2 or SEQ ID NO:4 having amino acid substitutions at positionsMet146, His163, Leu171, Ala246, Ala260, Ala285, Leu286, Leu392, and/orCys410.
 21. The presenilin-1 protein of claim 20, in which the Metresidue at position 146 of SEQ ID NO:2 or SEQ ID NO:4 is substituted byLeu.
 22. The presenilin-1 protein of claim 20, in which the His residueat position 163 of SEQ ID NO:2 or SEQ ID NO:4 is substituted by Arg. 23.The presenilin-1 protein of claim 20, in which the Leu residue atposition 171 of SEQ ID NO:2 or SEQ ID NO:4 is substituted by Pro. 24.The presenilin-1 protein of claim 20, in which the Ala residue atposition 246 of SEQ ID NO:2 or SEQ ID NO:4 is substituted by Glu. 25.The presenilin-1 protein of claim 20, in which the Ala residue atposition 260 of SEQ ID NO:2 or SEQ ID NO:4 is substituted by Val. 26.The presenilin-1 protein of claim 20, in which the Ala residue atposition 285 of SEQ ID NO:2 or SEQ ID NO:4 is substituted by Val. 27.The presenilin-1 protein of claim 20, in which the Leu residue atposition 286 of SEQ ID NO:2 or SEQ ID NO:4 is substituted by Val. 28.The presenilin-1 protein of claim 20, in which the Leu residue atposition 392 of SEQ ID NO:2 or SEQ ID NO:4 is substituted by Val. 29.The presenilin-1 protein of claim 20, in which the Cys residue atposition 410 of SEQ ID NO:2 or SEQ ID NO:4 is substituted by Tyr.